Novel glp-1 receptor modulators

ABSTRACT

Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “ ” represents either or both the R and S form of the compound): 
     
       
         
         
             
             
         
       
     
     where A, B, C, Y 1 , Y 2 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , W 1 , n, p and q are as defined herein.

FIELD OF THE INVENTION

The invention relates to compounds that bind the glucagon-like peptide 1(GLP-1) receptor, methods of their synthesis, and methods of theirtherapeutic and/or prophylactic use. The present invention is directedto compounds adapted to act as modulators of the GLP-1 receptor, andpotentiators of incretin peptides, such as GLP-1(7-36) and GLP-1(9-36),as well as peptide-based therapies such as exenatide and liraglutide.

BACKGROUND

Glucagon-like peptide 1 receptor (GLP-1R) belongs to Family B1 of theseven-transmembrane G protein-coupled receptors, and its natural agonistligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 isa peptide hormone arising by its alternative enzymatic cleavage fromproglucagon, the prohormone precursor for GLP-1, which is highlyexpressed in enteroendocrine cells of the intestine, the alpha cells ofthe endocrine pancreas (islets of Langerhans), and the brain (Kieffer T.J. and Habener, J. F. Endocrin. Rev. 20:876-913 (1999); Drucker, D. J.,Endocrinology 142:521-7 (2001); Holst, J. J., Diabetes Metab. Res. Rev.18:430-41 (2002)). The initial actions of GLP-1 observed were on theinsulin-producing cells of the islets, where it stimulatesglucose-dependent insulin secretion. Subsequently, multiple additionalantidiabetogenic actions of GLP-1 were discovered including thestimulation of the growth and inhibition of the apoptosis of pancreaticbeta cells (Drucker, D. J., Endocrinology 144:5145-8 (2003); Holz, G. G.and Chepurny O. G., Curr. Med. Chem. 10:2471-83 (2003); List, J. F. andHabener, J. F., Am. J. Physiol. Endocrinol. Metab. 286:E875-81 (2004)).

On activation, GLP-1 receptors couple to the α-subunit of G protein,with subsequent activation of adenylate cyclase and increase of cAMPlevels, thereby potentiating glucose-stimulated insulin secretion.Therefore, GLP-1 is an attractive therapeutic target to lower bloodglucose and preserve the β-cells of the pancreas of diabetic patients.Glucagon has been used for decades in medical practice within diabetesand several glucagon-like peptides are being developed for varioustherapeutic indications. GLP-1 analogs and derivatives are beingdeveloped for the treatment for patients suffering from diabetes.

SUMMARY OF THE INVENTION

The present invention is directed to compounds adapted to act aspotentiators or modulators of GLP-1 receptor; methods of theirpreparation and methods of their use, such as in treatment of amalcondition mediated by GLP-1 receptor activation, or when modulationor potentiation of GLP-1 receptor is medically indicated.

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

wherein

A is a 5-, 6- or 7-membered heterocyclyl having one, two or threeheteroatoms where each such heteroatom is independently selected from O,N, and S, and where any ring atom of such heterocyclyl may be optionallysubstituted with one or more of R₄;

B is aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;

C is aryl, aralkyl, heterocyclyl or heterocyclylalkyl, and when C isaryl A and C may be taken together to form a fused bicyclic ring systembetween the 5-, 6- or 7-membered heterocyclyl of A and the aryl of C;

Y₁ and Y₂ are both null, or one of Y₁ or Y₂ is —NH— or —O— and the otherY₁ or Y₂ is null;

Z is —C(O)— or —S(O)₂—;

each R₁ is independently H or C₁₋₄ alkyl;

R₂ is —OH, —O—R₈, —N(R₁)—SO₂—R₇, —NR₄₁R₄₂,—N(R₁)—(CR_(a)R_(b))_(m)—COOR₈, —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)C(O)O(R₈),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, or—N(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl, which heterocyclyl may beoptionally (singly or multiply) substituted with R₇;

each R₃ and R₄ is independently H, halo, alkyl, alkyl substituted(singly or multiply) with R₃₁, alkoxy, haloalkyl, perhaloalkyl,haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂,—NR₁R₇, —C(O)R₇, —C(O)NR₁R₇, —NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇,—OS(O)₂R₇, —S(O)₂NR₁R₇, —NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈; or any two R₃ or R₄ groupson the same carbon atom taken together form oxo;

each R₃₁ is independently H, halo, hydroxyl, —NR₄₁R₄₂, or alkoxy;

each R₄₀ is independently H, R₇, alkyl which may be optionally (singlyor multiply) substituted with R₇, or R₄₀ and R₁ taken together with theN atom to which they are attached form a 3- to 7-membered heterocyclylwhich may be optionally (singly or multiply) substituted with R₇;

each R₄₁ and R₄₂ is independently R₄₀, —(CHR₄₀)_(n)—C(O)O—R₄₀,—(CHR₄₀)_(n)—C(O)—R₄₀, —(CH₂)_(n)—N(R₁)(R₇), aryl or heteroaryl any ofwhich aryl or heteroaryl may be optionally (singly or multiply)substituted with R₇; or any two R₄₁ and R₄₂ taken together with the Natom to which they are attached form a 3- to 7-membered heterocyclylwhich may be optionally (singly or multiply) substituted with R₇;

W₁ is null or -L-(CR_(a)R_(b))_(m)-L₁-R₆;

each L₁ is independently, from the proximal to distal end of thestructure of Formula I-R or I-S, null, —C(O)O—, —S(O₂)—, —S(O)—, —S—,—N(R₁)—C(O)—N(R₁)—, —N(R₁)—C(O)—O—, —C(O)— or —S(O₂)—NR₁—;

each R_(a) and R_(b) is independently H, halo, alkyl, alkoxy, aryl,aralkyl, heterocyclyl, heterocyclylalkyl (any of which alkyl, alkoxy,aryl, aralkyl, heterocyclyl or heterocyclylalkyl may be optionally(singly or multiply) substituted with R₇), —(CHR₄₀)_(m)C(O)OR₄₀,—(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀, —(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)—NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)OR₄₀, or —(CHR₄₀)_(m)—S—S—R₄₀; orany two R_(a) and R_(b) taken together with the carbon atom(s) to whichthey are attached form a cycloalkyl or heterocyclyl optionallysubstituted (singly or multiply) with R₇; or R₁ and any one of R_(a) orR_(b) taken together with the atoms to which they are attached formheterocyclyl optionally substituted (singly or multiply) with R₇;

R₅ is R₇, —(CR_(a)R_(b))_(m)—(CR_(a)R_(b))_(m)—R₇, or-(-L₃-(CR_(a)R_(b))_(r)-L₃-R₇, wherein the carbon atoms of any twoadjacent —(CR_(a)R_(b))_(m) or (CR_(a)R_(b))_(r) groups may be takentogether to form a double bond (—(C(R_(a))═(C(R_(a))—) or triple bond(—C≡C—);

R₆ is H, alkyl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, any ofwhich may be optionally substituted (singly or multiply) with R₇ or—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇;

each R₇ is independently R₁₀; a ring moiety selected from cycloalkyl,aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moietyis optionally (singly or multiply) substituted with R₁₀; or when acarbon atom bears two R₇ groups such two R₇ groups are taken together toform oxo or thioxo, or are taken together to form a ring moiety selectedfrom cycloalkyl, aryl, heterocyclyl or heterocyclyl, wherein such ringmoiety is optionally singly or multiply substituted with R₁₀;

each R₁₀ is independently H, halo, alkyl, haloalkyl, perhaloalkyl,—(CR_(a)R_(b))_(m)OH, —(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN,—(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈,—(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁S(O)₂R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,—(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈ or—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈;

each R₈ is independently H, alkyl, aryl,—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₁ or-(-L₃-(CR_(a)R_(b))_(r)—)_(s)-L₃-R₁;

L₂ is independently, from the proximal to distal end of the structure ofFormula I-R or I-S, null, —O—, —OC(O)—, —NR₁—, —C(O)NR₁—, —N(R₁)—C(O)—,—S(O₂)—, —S(O)—, —S—, —C(O)— or —S(O₂)—N(R₁)—;

each L₃ is independently null, —O—, or —N(R₁)—

each m is independently 0, 1, 2, 3, 4, 5 or 6;

each n is independently 0 or 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

each r is independently 2, 3, or 4; and

each s is independently 1, 2, 3, or 4.

In certain embodiments, a pharmaceutical composition comprising acompound of the invention together with at least one pharmaceuticallyacceptable carrier, diluent or excipient is provided.

In certain embodiments, a method of use of a compound of the inventioncomprising preparation of a medicament is provided.

In certain embodiments, the invention provides a pharmaceuticalcombination comprising a compound of the invention and a secondmedicament. In various such embodiments, the second medicament is anagonist or modulator for glucagon receptor, GIP receptor, GLP-2receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various embodiment, the second medicament ismedically indicated for the treatment of type II diabetes. In variousembodiments, the second medicament is a biguanide, a sulfonylurea, ameglitinide, a thiazolidinedione, an α-glucosidase inhibitor, a bileacid sequestrant, and/or a dopamine-2 agonist, and in more specificembodiments is metformin (a biguanide) or sitagliptin (a DPPIVinhibitor).

In certain embodiments, a method of activation, potentiation or agonismof a GLP-1 receptor is provided comprising contacting the receptor witha compound, pharmaceutical composition or pharmaceutical combination ofthe invention.

In certain embodiments, a method is provided for treatment of amalcondition in a subject for which activation, potentiation or agonismof a GLP-1 receptor is medically indicated where such method comprisesadministering to such subject a compound, pharmaceutical composition orpharmaceutical combination of the invention. In various suchembodiments, selective activation, potentiation or agonism of a GLP-1receptor, is medically indicated. In various such embodiments, themalcondition comprises type I diabetes, type II diabetes, gestationaldiabetes, obesity, excessive appetite, insufficient satiety, ormetabolic disorder.

In certain embodiments, the invention provides methods for synthesis ofcertain compounds including compounds of the invention. In certain otherembodiments, the invention provides certain intermediate compoundsassociated with such methods of synthesis.

DETAILED DESCRIPTION OF THE INVENTION

Certain embodiments comprise a compound having the chiral structure ofFormula I-R or I-S (with the chirality as indicated) or apharmaceutically acceptable isomer, enantiomer, racemate, salt, isotope,prodrug, hydrate or solvate thereof:

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

where A, B, C, Y₁, Y₂, Z, R₁, R₂, R₃, R₄, R₅, W₁, n, p and q are asdefined above. In certain embodiments, the compounds have the structureof Formula I-R or a pharmaceutically acceptable isomer, enantiomer,salt, isotope, prodrug, hydrate or solvate thereof. In otherembodiments, the compounds have the structure of Formula I-S or apharmaceutically acceptable isomer, enantiomer, salt, isotope, prodrug,hydrate or solvate thereof.

In certain embodiments, the compounds can be substantiallyenantiomerically pure.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and A is a 5-or 6-membered heteroaryl group. Representative compounds of thisembodiment include compounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound where Y₁ andY₂ are null, Z is —C(O)— and A is a 5-, 6- or 7-membered non-aromaticheterocyclyl group. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(29) where R₄ of the phenyl group is H.

In certain embodiments, the inventions provides compounds of each ofstructures I-R/S (1)-(29) where the A group (i.e., the 5-, 6- or7-membered heterocyclyl) is not substituted by R₄, or substituted by R₄where R₄ is alkyl, haloalkyl, alkoxy, —NR₁R₇ where R₁ and R₇ areindependently hydrogen or alkyl, or substituted by two R₄ groups whichtaken together form oxo.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and C is aryl.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (30)-(32) where q is zero.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (30)-(32) where q is one, two or three.

In certain embodiments, the invention provides compounds of structureI-R/S (30) where q is one and R₅ is—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇ or-(-L₃-(CR_(a)R_(b))_(r)—)_(s)-L₃-R₇. Representative compounds of thisembodiment include compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (33) where R₇ is H or alkyl and L₂ is O. Representative compoundsof this embodiment include compounds of the following structure (wherein“

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (30) where R₅ is R₇. Representative compounds of this embodimentsinclude compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (35) where R₇ is halo, alkyl, haloalkyl, perhaloalkyl, alkoxy,—(CR_(a)R_(b))_(m)OH, —(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN,—(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈,—(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,—(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈,—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈.

In certain embodiments, the invention provides compounds of structureI-R/S (35) where R₇ is a ring moiety selected from cycloalkyl, aryl,aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moiety isoptionally (singly or multiply) substituted with halo, —OH, —CN, alkyl,alkoxy, haloalkyl or perhaloalkyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and C isheterocyclyl. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (36)-(44) where R₇ is halo, alkyl, haloalkyl,perhaloalkyl, alkoxy, —(CR_(a)R_(b))_(m)OH, —(CR_(a)R_(b))_(m)OR₈,—(CR_(a)R_(b))_(m)CN, —(CR_(a)R_(b))_(m)NH(C═NH)NH₂,—(CR_(a)R_(b))_(m)NR₁R₈, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈,—(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,—(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈,—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (36)-(44) where R₇ is a ring moiety selected fromcycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where suchring moiety is optionally (singly or multiply) substituted with halo,—OH, —CN, alkyl, alkoxy, haloalkyl or perhaloalkyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and B is arylor aralkyl. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (45)-(48) where W₁ is null.

Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (49) where R₃ is halo, alkyl, alkyl substituted with R₃₁, alkoxy,haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heterocyclyl,—OH, —OR₇, —CN, —NO₂, —NR₁R₇, —C(O)R₇, —C(O)NR₁R₇, —NR₁C(O)R₇, —SR₇,—S(O)R₇, —S(O)₂R₇, —OS(O)₂R₇, —S(O)₂NR₁R₇, —NR₁S(O)₂R₇,—(CR_(a)R_(b))_(m)NR₁R₇, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (45)-(49) where R₃ is alkyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and B isheterocyclyl or heterocyclylalkyl. Representative compounds of thisembodiment include compounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (50)-(62) where W₁ is null.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (50)-(62) where W₁ is null and R₃ is halo, alkyl, alkylsubstituted with R₃₁, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy,perhaloalkoxy, aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂, —NR₁R₇,—C(O)R₇, —C(O)NR₁R₇, —NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇, —OS(O)₂R₇,—S(O)₂NR₁R₇, —NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇, —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or —(CR_(a)R_(b))_(m)NR(CR_(a)R_(b)).

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (50)-(62) where W₁ is null, p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(62) where R₂ is —OH, —N(R₁)—(CR_(a)R_(b))_(m)—COOHor —N(R₁)—SO₂—R₇; where R₁ is H; where R_(a) and R_(b) are independentlyH, alkyl, alkoxy, —(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)OR₄₀,—(CHR₄₀)_(m)NR₄₁R₄₂, —(CHR₄₀)_(m)SR₄₀, aryl optionally substituted withR₇, or wherein R₁ and any one of R_(a) or R_(b) taken together with thecarbon(s) to which they are attached form heterocyclyl; R₈ is alkyl; andm is 1 or 2.

In certain embodiments, the invention provides compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (63) where A is a 5-membered heteroaryl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where A is a 6-membered heteroaryl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where A is a 6-membered heteroaryl having one or two nitrogenatoms.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where A is pyrimindinyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where A is pyridinyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where B is aryl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where B is phenyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where B is heteroaryl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where B is thiophenyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —OH.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)COOR₈.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —N(R₁)SO₂R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —NHCH₂COOH.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —NH(CHR_(b))COOH where R_(b) is alkyl optionallysubstituted with R₇, —(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀,—(CHR₄₀)_(m)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)—NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)OR₄₀ or —(CHR₄₀)_(m)—S—S—R₄₀

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —NH(CR_(a)R_(b))_(m)COOH where R_(a) and R_(b)are independently H, alkyl optionally substituted with R₇,—(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀, —(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)—NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)OR₄₀ or —(CHR₄₀)_(m)—S—S—R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —NR₁(CHR_(b))_(m)COOH where R₁ and R_(b) takentogether form heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH where R₁ and one ofR_(b) taken together form heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where any two R_(a) and R_(b) taken together with the carbonto which they are attached form a cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where R₂ is —NH(CR_(a)R_(b))_(m)COOH where one of R_(a) andR_(b) is H and the other R_(a) and R_(b) is aryl substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where p is 1 or 2 and each R₃ is independently alkyl, alkoxy,—OH, perhaloalkyl or .C(O)R₈.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where p is 1 and each R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where q is 1 and R₅ is—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇, and in more specificembodiments where q is 1 and R₅ is —(CH₂)_(m)-L₂-(CH₂)_(m)—R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (63) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (64) where B is phenyl or thiophenyl. Representative compounds ofthis embodiment include compounds of the following structure (wherein “

” represents e Ter or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is C₆₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is C₆ alkoxy

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is C₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is C₁₋₄ alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where q is 1 and R₅ is cyclopropyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is alkyl, q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₄₋₈alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₆₋₈alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₆alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₇alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₈alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₁₋₄alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ iscycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where p is 1, R₃ is tert-butyl, q is 1 and R₅ iscyclopropyl.

In certain embodiments, the invention provides compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (64-1) where B is phenyl or thiophenyl. Representative compoundsof this embodiment include compounds of the following structure (wherein“

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl (—CH₂phenyl), phenylethyl(—CH₂CH₂phenyl) or phenylethylene (—CH═CHphenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl (—CH₂phenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is phenylethyl (—CH₂CH₂phenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is phenylethylene (—CH═CHphenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is C₆₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is C₆ alkoxy

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is C₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is C₁₋₄ alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where q is 1 and R₅ is cyclopropyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is alkyl, q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₆₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₆ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is phenylethylene, p is 1, R₃ istert-butyl, q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is phenylethylene, p is 1, R₃ istert-butyl, q is 1 and R₅ is C₁₋₄ alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is cyclopropyl.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)(CR_(a)R_(b))_(m)COOR₈. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65-1)-(66-1) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)COOR₈.Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where R₁ is hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where R₈ is hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where m is 2, R₁ is hydrogen, eachoccurrence of R_(a) and R_(b) are hydrogen, and R₈ is hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where m is 2, a single R_(a) (i.e.,one of the two) is hydrogen, each occurrence of R_(b) is hydrogen, andR₈ is hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where m is 1 and R₁, R_(a), R_(b)and R₈ are hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where m is 1, R_(a) is alkyl and R₁,R_(b) and R₈ are hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where m is 1, R_(a) is methyl andR₁, R_(b) and R₈ are hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl (—CH₂phenyl), phenylethyl(—CH₂CH₂phenyl) or phenylethylene (—CH═CHphenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl (—CH₂phenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is phenylethyl (—CH₂CH₂phenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is phenylethylene (—CH═CHphenyl).

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is C₆₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is C₆ alkoxy

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is C₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is C₁₋₄ alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67), (67-1), (68) and (68-1) where q is 1 and R₅ is cyclopropyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is alkyl, q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₆₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₆ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is C₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is phenylethylene, p is 1, R₃ istert-butyl, q is 1 and R₅ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is phenylethylene, p is 1, R₃ istert-butyl, q is 1 and R₅ is C₁₋₄ alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67-1)-(68-1) where aralkyl is benzyl, phenylethyl orphenylethylene, p is 1, R₃ is tert-butyl, q is 1 and R₅ is cyclopropyl.

In certain embodiments, the invention provides compounds of structureI-R/S (67)-(68) where m is 2, R₁ is hydrogen, each occurrence of R_(a)and R_(b) are hydrogen, and R₈ is hydrogen. Representative compounds ofthis embodiment include compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (69)-(70) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (69)-(70) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (69)-(70) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (69)-(70) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (69)-(70) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (69)-(70) where p is 1, R₃ is alkyl, q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67)-(68) where m is 1 and R₁, R_(b) and R₈ are hydrogen.Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (67)-(68) where m is 2, a single R_(a) (i.e., one of the two) ishydrogen, each occurrence of R_(b) is hydrogen, and R₈ is hydrogen.Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is alkyl optionally substituted with R₇,wherein alkyl includes straight and branched alkyl groups such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl andtert-butyl, as well as cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl or tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is methyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is heterocycle or heterocyclylalkyl, eitherwhich may be optionally substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is heterocycle, such as pyrazinyl,pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl,hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl,furanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl,piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl, any of which maybe optionally substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is aryl or aralkyl, either of which may beoptionally substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is aryl or aralkyl, such as phenyl orbenzyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is aryl or heteroaryl substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is phenyl or benzyl substituted withhydroxyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —CH(OH)C₆H₅.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)C(O)OH.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)OH.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —CH₂OH.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)SR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)SR₄₀, where R₄₀ is H or alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —CH₂C(O)NH₂ or —CH₂CH₂C(O)NH₂

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)C(O)N(R₁)(CH₂)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)C(O)N(R₁)(CH₂)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)C(O)N(R₁)(CH₂)_(m)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CHR₄₀)_(m)—S—S—R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where R_(a) is —(CH₂)_(m)—S—S—R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) wherein, within the R_(a) group, R₁, R₄₀, R₄₁ and R₄₂are hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) wherein, within the R_(a) group, m is 1.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) wherein, within the R_(a) group, m is 2.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (71)-(74) where p is 1, R₃ is alkyl, q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (67)-(68) where m is 1, R_(b) is hydrogen and R₁ and R_(a) takentogether with the atoms to which they are attached form a heterocyclyloptionally substituted (singly or multiply) with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (67)-(68) where m is 2, R_(b) of the second (CR_(a)R_(b)) group ishydrogen and R₁ and R_(a) of the second (CR_(a)R_(b)) group takentogether with the atoms to which they are attached form a heterocyclyloptionally substituted (singly or multiply) with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(78) where R₁ and R_(a) taken together with the atoms towhich they are attached form azetidinyl, pyrrolindinyl, piperidinyloptionally substituted (singly or multiply) with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where p is 1, R₃ is alkyl, q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where R₇ is absent.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where R₇ is hydroxyl.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where R₇ is absent, p is 1, R₃ is alkyl, q is 1 and R₅is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (75)-(86) where R₇ is hydroxyl, p is 1, R₃ is alkyl, q is 1 and R₅is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)—SO₂—R₈. Representative compounds ofthis embodiment include compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (87)-(88) where R₁ is hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (87)-(88) where R₁ is hydrogen an R₈ is alkyl optionallysubstituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is —OH. Representative compounds of thisembodiment include compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)(R₄₂). Representative compounds of thisembodiment include compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ and R₄₂ are independently R₄₀,—(CHR₄₀)_(n)—C(O)OR₄₀, —(CHR₄₀)_(n)—C(O)R₄₀, —(CH₂)_(n)N(R₁)(R₇), arylor heteroaryl, which aryl or heteroaryl is optionally substituted(singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ is hydrogen and R₄₂ is alkyl optionallysubstituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ is hydrogen and R₄₂ is —(CHR₄₀)_(n)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ is hydrogen and R₄₂ is —(CHR₄₀)_(n)C(O)R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ is hydrogen and R₄₂ is —(CH₂)_(n)N(R₁)(R₇).

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ is hydrogen and R₄₂ is aryl optionallysubstituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ is hydrogen and R₄₂ is heteroaryl optionallysubstituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ and R₄₂ taken together with the N atom towhich they are attached form a 3- to 7-membered heterocyclyl optionallysubstituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (91)-(92) where R₄₁ and R₄₂ taken together with the N atom towhich they are attached form pyrazinyl, pyrimidinyl, pyridazinyl,thiadiazolyl, oxadiazolyl, imidazolinyl, hexahydropyrimidinyl,diazepanyl, triazinyl, imidazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl or pyridinyl, any of which may beoptionally substituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)(CR_(a)R_(b))_(m)CON(R₁)(R₄₀).Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(94) where m is 1, R_(b) is hydrogen and R₁ and R_(a) takentogether with the atoms to which they are attached form a heterocyclyloptionally substituted (singly or multiply) with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(94) where m is 2, R_(b) of the second (CR_(a)R_(b)) group ishydrogen and R₁ and R_(a) of the second (CR_(a)R_(b)) group takentogether with the atoms to which they are attached form a heterocyclyloptionally substituted (singly or multiply) with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (95)-(98) where R₁ and R_(a) taken together with the atoms towhich they are attached form azetidinyl, pyrrolindinyl, piperidinyloptionally substituted (singly or multiply) with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where p is 1 and R₃ is tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where q is 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where q is 1 and R₅ is C₇ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where p is 1, R₃ is alkyl, q is 1 and R₅ is C_(4-g)alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where R₇ is absent or hydroxyl.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where R₇ is absent or hydroxyl, p is 1, R₃ is alkyl, qis 1 and R₅ is C₄₋₈ alkoxy.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where R₁ is hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where R₄₀ is R₇.

In certain embodiments, the invention provides compounds of structureI-R/S (93)-(104) where R₄₀ is R₇, R₇ is —(CR_(a)R_(b))_(m)S(O)₂R₈, andR₈ is —(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₁.

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)(CR_(a)R_(b))_(m)N(R₁)C(O)O(R₈).Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)(CR_(a)R_(b))_(m)N(R₁)(R₇).Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)CON(R₁)heterocyclyl.Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (65)-(66) where R₂ is-N(R₁)(CR_(a)R_(b))_(m)-heterocyclyl, whichheterocyclyl may be optionally substituted with R₇. Representativecompounds of this embodiment include compounds of the followingstructure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structuresI-R/S (65-1)-(66-1) where R₂ is as shown in each of structures I-R/S(69) through I-R/S (112). Such compounds are referred to herein as I-R/S(69-1) through I-R/S (112-1). For example, structures I-R/S(67-1)-(68-1) depict structures I-R/S (65-1)-(66-1) when R₂ is—N(R₁)(CR_(a)R_(b))_(m)COOR₈. In a similar manner, structures I-R/S(69-1) through I-R/S (112-1) correspond to structures I-R/S (69) throughI-R/S (112), but with the specific R₂ group of structures I-R/S (69)through I-R/S (112) serving as the R₂ group of structures I-R/S(65-1)-(66-1).

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null and Z is —S(O)₂—.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (95) where A is pyrimidinyl, B is phenyl and C is phenyl.Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ is null, Y₂ is —O— and Z is —C(O)—.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ is NH, Y₂ is null and Z is —C(O)—.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where C is aryl and A and C are taken together toform a fused bicyclic ring system between the 5-, 6- or 7-memberedheterocyclyl of A and the aryl of C. Representative compounds of thisembodiment include compounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S (99) where Y₁ is null and Z is —C(O)—. Representative compounds ofthis embodiment include compounds of the following structures where oneor both of X_(A) and X_(B) is nitrogen (wherein “

” represents either or both the R and S form of the compound)

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention together with atleast one pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament. In certain of such embodiments, the second medicament is aGLP-1 agonist or a DPPIV inhibitor.

In certain embodiments, the invention provides a method of use ofcompounds of the invention for preparation of a medicament.

In certain embodiments, the invention provides a pharmaceuticalcombination comprising a compound of the invention and a secondmedicament. In various such embodiments, the second medicament is anagonist or modulator for glucagon receptor, GIP receptor, GLP-2receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating petptide. In various such embodiments, the second medicamentis a DPPIV inhibitor, such as sitagliptin. In various such embodiments,the second medicament is medically indicated for the treatment of typeII diabetes. In various combinations, the second medicament is asodium-glucose co-transporter (SGLT) inhibitor, such as a SGLT1 and/orSGLT2 inhibitor. In various such embodiments, the second medicament is abiguanide such as metformin, a sulfonylurea such as glibenclamide,glipizide, gliclazide, and glimepiride, a meglitinide such asrepaglinide and mateglinide, a thiazolidinedione such as pioglitazoneand rosiglitazone, an α-glucosidase inhibitor such as acarbose andmiglitol, a bile acid sequestrant such as colesevelam, and/or adopamine-2 agonist such as bromocriptine.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament, wherein the second medicament is metformin.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament, wherein the second medicament is sitagliptin.

In certain embodiments, a method is provided for activation,potentiation or agonism of a glucagon-like peptide 1 comprisingcontacting the receptor with an effective amount of a compound,pharmaceutical composition or pharmaceutical combination of theinvention.

In further embodiments, a method is provided for activation or agonismof a GLP-1 receptor by contacting the receptor with an effective amountof an invention compound and GLP-1 peptides GLP-1(9-36) and GLP-1(7-36),pharmaceutical composition or pharmaceutical combination, wherein theGLP-1 receptor is disposed within a living mammal; in certainembodiments wherein such mammal is a human.

In certain embodiments, a method is provided for treatment of amalcondition in a subject for which activation, potentiation or agonismof a GLP-1 receptor is medically indicated, by administering aneffective amount of an invention compound to the subject at a frequencyand for a duration of time sufficient to provide a beneficial effect tothe patient. In yet further embodiments, a method is provided fortreatment of a malcondition in a patient for which activation,potentiation, or agonism of a GLP-1 receptor is medically indicated, byadministering an effective amount of an invention compound to thepatient at a frequency and for a duration of time sufficient to providea beneficial effect to the patient, wherein the malcondition comprisestype I diabetes, type II diabetes, gestational diabetes, obesity,excessive appetite, insufficient satiety, or metabolic disorder. Incertain embodiments, the subject is a patient or a human being. Incertain embodiments, the human being is afflicted with, or at risk ofdeveloping, a disease or condition selected from the group consisting oftype I diabetes, type II diabetes, gestational diabetes, obesity,excessive appetite, insufficient satiety, and metabolic disorder. Incertain of such embodiments, said disease is type I diabetes or type IIdiabetes.

In certain embodiments, the invention provides methods for synthesis ofcertain compounds including compounds of the invention as more fullyillustrated herein. In certain other embodiments, the invention providescertain intermediate compounds associated with such methods of synthesisas illustrated herein.

In certain embodiments, methods are provided for use of an inventioncompound for preparation of a medicament adapted for treatment of adisorder or a malcondition wherein activation or inhibition of a GLP-1receptor is medically indicated. In certain embodiments, themalcondition comprises type I diabetes, type II diabetes, gestationaldiabetes, obesity, excessive appetite, insufficient satiety, andmetabolic disorder. Preferably said disease is type I diabetes or typeII diabetes.

In certain embodiments, the method additionally comprises administeringto the subject a second medicament selected from the group ofbiguanides, peptidic GLP-1 agonists and DPPIV inhibitors, wherein suchsecond medicament is either a component of the pharmaceuticalcomposition or a second pharmaceutical composition. In certain of suchembodiments, the second medicament can be metformin, exenatide orsitagliptin.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

As used herein, “individual” (as in the subject of the treatment) meansboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g., apes and monkeys; cattle; horses; sheep; andgoats. Non-mammals include, for example, fish and birds.

A “receptor”, as is well known in the art, is a biomolecular entityusually comprising a protein that specifically binds a structural classof ligands or a single native ligand in a living organism, the bindingof which causes the receptor to transduce the binding signal intoanother kind of biological action, such as signaling a cell that abinding event has occurred, which causes the cell to alter its functionin some manner. An example of transduction is receptor binding of aligand causing alteration of the activity of a “G-protein” in thecytoplasm of a living cell. Any molecule, naturally occurring or not,that binds to a receptor and activates it for signal transduction, isreferred to as an “agonist” or “activator.” Any molecule, naturallyoccurring or not, that binds to a receptor, but does not cause signaltransduction to occur, and which can block the binding of an agonist andits consequent signal transduction, is referred to as an “antagonist.”Certain molecules bind to receptors at locations other than the bindingsites of their natural ligands and such allosteric binding molecules maypotentiate, activate or agonize the receptor and may enhance the effectof a natural ligand or a co-administered ligand.

A “GLP-1 compound” or “GLP-1 agonist” or “GLP-1 activator” or “GLP-1inhibitor” or “GLP-1 antagonist” or “GLP-1 potentiator” or “GLP-1modulator” as the terms are used herein refer to compounds that interactin some way with the GLP-1 receptor. They can be agonists, potentiators,or activators, or they can be antagonists or inhibitors. A “GLP-1compound” of the invention can be selective for action of the GLP-1receptor family.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

Substantially enantiomerically or diasteromerically pure means a levelof enantiomeric or diasteromeric enrichment of one enantiomer withrespect to the other enantiomer or diasteromer of at least about 80%,and more preferably in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or99.9%.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder.

The expression “effective amount”, when used to describe use of acompound of the invention in providing therapy to a patient sufferingfrom a disorder or malcondition mediated by GLP-1 refers to the amountof a compound of the invention that is effective to bind to as anagonist or as an antagonist a GLP-1 receptor in the individual'stissues, wherein the GLP-1 is implicated in the disorder, wherein suchbinding occurs to an extent sufficient to produce a beneficialtherapeutic effect on the patient. Similarly, as used herein, an“effective amount” or a “therapeutically effective amount” of a compoundof the invention refers to an amount of the compound that alleviates, inwhole or in part, symptoms associated with the disorder or condition, orhalts or slows further progression or worsening of those symptoms, orprevents or provides prophylaxis for the disorder or condition. Inparticular, a “therapeutically effective amount” refers to an amounteffective, at dosages and for periods of time necessary, to achieve thedesired therapeutic result by acting as an agonist of GLP-1 activity. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects. For example, in the context oftreating a malcondition mediated by activation of a GLP-1 receptor, atherapeutically effective amount of a GLP-1 receptor agonist of theinvention is an amount sufficient to control the malcondition, tomitigate the progress of the malcondition, or to relieve the symptoms ofthe malcondition. Examples of malconditions that can be so treatedinclude, but not limited to, type II diabetes.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be synthesized so as to be substantially free of their enantiomericor diastereomeric partners, and these are all within the scope ofcertain embodiments of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.Once the priority ranking of the four groups is determined, the moleculeis oriented so that the lowest ranking group is pointed away from theviewer. Then, if the descending rank order of the other groups proceedsclockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated(S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking isA>B>C>D. The lowest ranking atom, D is oriented away from the viewer.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, and preferably atleast 80% or even at least 85% pure. In other embodiments, the isolatedisomer is at least 90% pure or at least 98% pure, or at least about 99%pure, by weight.

Enantiomers are sometimes called optical isomers because a pureenantiomer rotates plane-polarized light in a particular direction. Ifthe light rotates clockwise, then that enantiomer is labeled “(+)” or“d” for dextrorotatory, its counterpart will rotate the lightcounterclockwise and is labeled “(−)” or “1” for levorotatory.

The terms “racemate” and “racemic mixture” are frequently usedinterchangeably. A racemate is an equal mixture of two enantiomers. Aracemate is labeled “(±)” because it is not optically active (i.e., willnot rotate plane-polarized light in either direction since itsconstituent enantiomers cancel each other out).

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species, example shown below. It isfurther understood that certain structural elements, including stericbulk or substituents on the amide nitrogen, may enhance the stability ofa rotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present inventiontherefore includes any possible stable rotamers of compounds of theinvention which are biologically active in the treatment of type Idiabetes, type II diabetes, gestational diabetes, obesity, excessiveappetite, insufficient satiety, or metabolic disorder.

The preferred compounds of the present invention have a particularspatial arrangement of substituents on the aromatic rings, which arerelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

All structures encompassed within a claim are “chemically feasible”, bywhich is meant that the structure depicted by any combination orsubcombination of optional substituents meant to be recited by the claimis physically capable of existence with at least some stability as canbe determined by the laws of structural chemistry and byexperimentation. Structures that are not chemically feasible are notwithin a claimed set of compounds. Further, isotopes of the atomsdepicted (such as deuterium and tritium in the case of hydrogen) areencompassed within the scope of this invention.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboyxlate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents that can bebonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, CF₃, OCF₃, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R′)₂, SO₃R′, C(O)R′,C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′)₂,OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′, (CH₂)O₂N(R′)N(R′)₂,N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′,N(R′)SO₂N(R′)₂, N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′ wherein R′ can be hydrogen or a carbon-based moiety, andwherein the carbon-based moiety can itself be further substituted.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups include substituted aryl, heterocyclyl andheteroaryl groups. Substituted ring groups can be substituted by one ormore substituents at any available ring position. In some embodiments,two substituents on a substituted ring group may taken together with thering to which they are attached to form a ring, such that the two ringsare fused together. For example, benzodioxolyl is a fused ring systemformed by two substituents taken together on a phenyl group.

Such substituted ring groups also include rings and fused ring systemsin which a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted aryl, heterocyclyl and heteroaryl groupscan also be substituted with alkyl, alkenyl, cycloalkyl, aryl,heteroaryl, and alkynyl groups as defined herein, which can themselvesbe further substituted.

The linking groups (e.g., L₁ and L₂) of Formula I-R or I-S are partialstructures which may be represented by a formula, say, for example,—N(R₁)—C(O)—, which is read from left-to-right. Accordingly, thenitrogen atom of the —N(R₁)—C(O)— linker will be attached to theproximal end of the structure of Formula I-R or I-S, and the carbonylcarbon atom of the —N(R₁)—C(O)— linker will be attached to the distalend of the structure of Formula I-R or I-S.

The term “heteroatoms” as used herein refers to non-carbon andnon-hydrogen atoms, capable of forming covalent bonds with carbon, andis not otherwise limited. Typical heteroatoms are N, O, and S. Whensulfur (S) is referred to, it is understood that the sulfur can be inany of the oxidation states in which it is found, thus includingsulfoxides (R—S(O)—R′) and sulfones (R—S(O)₂—R′), unless the oxidationstate is specified; thus, the term “sulfone” encompasses only thesulfone form of sulfur; the term “sulfide” encompasses only the sulfide(R—S—R′) form of sulfur. When the phrases such as “heteroatoms selectedfrom the group consisting of O, NH, NR′ and S,” or “[variable] is O, S .. . ” are used, they are understood to encompass all of the sulfide,sulfoxide and sulfone oxidation states of sulfur.

Alkyl groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms, and typicallyfrom 1 to 12 carbons (C₁-C₁₂ alkyl), or, in some embodiments, from 1 to8 carbon atoms (C₁-C₈ alkyl), or, in some embodiments, from 1 to 4carbon atoms (C₁-C₄ alkyl). In the case of cycloalkyl groups, suchgroups have from 3-20 carbon atoms. Examples of straight chain alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples ofbranched alkyl groups include, but are not limited to, isopropyl,iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. Alkyl groups as used herein may optionallyinclude one or more further substituent groups. Representativesubstituted alkyl groups can be substituted one or more times with anyof the groups listed above, for example, amino, hydroxy, cyano, carboxy,nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring do notgive rise to aromaticity. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like. Cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups can be mono-substituted orsubstituted one or more times with any of the groups listed above, forexample, but not limited to, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups.

The terms “carbocyclic” and “carbocycle” denote a ring structure whereinthe atoms of the ring are carbon. In some embodiments, the carbocyclehas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms is 4, 5, 6, or 7. Unless specifically indicated to thecontrary, the carbocyclic ring can be substituted with as many as Nsubstituents wherein N is the size of the carbocyclic ring with forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to —CH═CH₂, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, —CH═CHCH₂CH₃, —CH═CH(CH₂)₂CH₃,—CH═CH(CH₂)₃CH₃, —CH═CH(CH₂)₄CH₃, vinyl, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

The term “cycloalkenyl” alone or in combination denotes a cyclic alkenylgroup wherein at least one double bond is present in the ring structure.Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between two adjacent carbon atoms. Thus for example, cycloalkenylgroups include but are not limited to cyclohexenyl, cyclopentenyl, andcyclohexadienyl groups, as well as polycyclic and/or bridging ringsystmes such as adamantine.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃), among others.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl,anthracenyl, and naphthyl groups. In some embodiments, aryl groupscontain 6-14 carbons in the ring portions of the groups. The phrase“aryl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), and also includes substituted aryl groups that have othergroups, including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring atoms.Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or naphthyl groups, which can be substitutedwith groups including but not limited to those listed above.

Aralkyl groups are alkyl, alkenyl or alkynyl groups as defined above inwhich a hydrogen atom of an alkyl, alkenyl or alkynyl group is replacedwith an aryl group as defined above. Representative aralkyl groupsinclude benzyl (—CH₂phenyl), phenylethyl (—CH₂CH₂phenyl) andphenylethylene (—CH═CHphenyl) groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl. The aryl moiety or the alkyl, alkenyl oralkynyl moiety or both are optionally substituted with other groups,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups.

Heterocyclyl or heterocyclic groups include aromatic and non-aromaticring moieties containing 3 or more ring members, of which one or more isa heteroatom such as, but not limited to, N, O, S, or P. In someembodiments, heterocyclyl groups include 3 to 20 ring members, whereasother such groups have 3 to 15 ring members, including for examplesingle ring systems containing 5, 6 or 7 ring members. At least one ringcontains a heteroatom, but every ring in a polycyclic system need notcontain a heteroatom. For example, a dioxolanyl ring and abenzdioxolanyl ring system (methylenedioxyphenyl ring system) are bothheterocyclyl groups within the meaning herein. A heterocyclyl groupdesignated as a C₂-heterocyclyl can be a 5-ring with two carbon atomsand three heteroatoms, a 6-ring with two carbon atoms and fourheteroatoms, and so forth. Likewise a C₄-heterocyclyl can be a 5-ringwith one heteroatom, a 6-ring with two heteroatoms, and so forth. Thenumber of carbon atoms plus the number of heteroatoms sums up to equalthe total number of ring atoms.

The term “heterocyclyl” includes fused ring species including thosehaving fused aromatic and non-aromatic groups. The phrase also includespolycyclic and/or bridging ring systems containing a heteroatom such as,but not limited to, quinuclidyl and 7-azabicyclo[2.2.1]heptane, and alsoincludes heterocyclyl groups that have substituents, including but notlimited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, oralkoxy groups, bonded to one of the ring members. A heterocyclyl groupas defined herein can be a heteroaryl group or a partially or completelysaturated cyclic group including at least one ring heteroatom.Heterocyclyl groups include, but are not limited to, pyrazinyl,pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl,hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl,furanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl,piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.Heterocyclyl groups can be substituted. Representative substitutedheterocyclyl groups can be mono-substituted or substituted more thanonce, including but not limited to, rings containing at least oneheteroatom which are mono, di, tri, tetra, penta, hexa, orhigher-substituted with substituents such as those listed above,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, and alkoxy groups, and in the case of twosubstituents on the same carbon atom of the heterocycle include oxo (═O)and thioxo (═S).

Heteroaryl groups are aromatic ring moieties containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. A heteroaryl group designated as a C₂-heteroaryl can bea 5-ring with two carbon atoms and three heteroatoms, a 6-ring with twocarbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroarylcan be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, andso forth. The number of carbon atoms plus the number of heteroatoms sumsup to equal the total number of ring atoms. Heteroaryl groups include,but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl,pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thiadiazolyl,imidazolyl, oxadiazolyl, thienyl, triazolyl, tetrazolyl, triazinyl,thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, andquinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups”include fused ring compounds such as wherein at least one ring, but notnecessarily all rings, are aromatic, including tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. The term alsoincludes heteroaryl groups that have other groups bonded to one of thering members, including but not limited to alkyl, halo, amino, hydroxy,cyano, carboxy, nitro, thio, or alkoxy groups. Representativesubstituted heteroaryl groups can be substituted one or more times withgroups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl(1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl(1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), isoxazolyl, quinazolinyl,fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl(1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), prazolo[1,5-a]pyridinyl, quinolyl(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl,8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl),benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl,4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl,7-benzo[b]furanyl), isobenzofuranyl, 2,3-dihydro-benzo[b]furanyl(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl),benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl,7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl,(2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl),4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl),6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl),indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl,5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl,6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl(1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl,2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,7-benzothiazolyl), benzo[d]isoxazolyl, carbazolyl (1-carbazolyl,2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl, alkenyl or alkynyl groups as definedabove in which a hydrogen or carbon bond of an alkyl, alkenyl or alkynylgroup is replaced with a bond to a heterocyclyl group as defined above.Representative heterocyclyl alkyl groups include, but are not limitedto, furan-2-yl methyl, furan-3-yl methyl, pyridine-2-yl methyl(α-picolyl), pyridine-3-yl methyl (β-picolyl), pyridine-4-yl methyl(γ-picolyl), tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.Heterocyclylalkyl groups can be substituted on the heterocyclyl moiety,the alkyl, alkenyl or alkynyl moiety, or both.

Heteroarylalkyl groups are alkyl, alkenyl or alkynyl groups as definedabove in which a hydrogen or carbon bond of an alkyl, alkenyl or alkynylgroup is replaced with a bond to a heteroaryl group as defined above.Heteroarylalkyl groups can be substituted on the heteroaryl moiety, thealkyl, alkenyl or alkynyl moiety, or both.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic. By “spirocyclic” is meant the class ofstructures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

A “monocyclic, bicyclic or polycyclic, aromatic or partially aromaticring” as the term is used herein refers to a ring system including anunsaturated ring possessing 4n+2 pi electrons, or a partially reduced(hydrogenated) form thereof. The aromatic or partially aromatic ring caninclude additional fused, bridged, or spiro rings that are notthemselves aromatic or partially aromatic. For example, naphthalene andtetrahydronaphthalene are both a “monocyclic, bicyclic or polycyclic,aromatic or partially aromatic ring” within the meaning herein. Also,for example, a benzo-[2.2.2]-bicyclooctane is also a “monocyclic,bicyclic or polycyclic, aromatic or partially aromatic ring” within themeaning herein, containing a phenyl ring fused to a bridged bicyclicsystem. A fully saturated ring has no double bonds therein, and iscarbocyclic or heterocyclic depending on the presence of heteroatomswithin the meaning herein.

When two “R” groups are said to be joined together or taken together toform a ring, it is meant that together with the carbon atom or anon-carbon atom (e.g., nitrogen atom), to which they are bonded, theymay form a ring system. In general, they are bonded to one another toform a 3- to 7-membered ring, or a 5- to 7-membered ring. Non-limitingspecific examples are the cyclopentyl, cyclohexyl, cycloheptyl,piperidinyl, piperazinyl, pyrolidinyl, pyrrolyl, pyridinyl.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy,n-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy n-nonyloxy,and the like. Examples of branched alkoxy include but are not limited toisopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and thelike. Examples of cyclic alkoxy include but are not limited tocyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃₊,wherein each R is independently selected, and protonated forms of each.Accordingly, any compound substituted with an amino group can be viewedas an amine.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄₊, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to carbamoyl groups (—C(O)NH₂) and formamidegroups (—NHC(O)H). A “carboxamido” group is a group of the formulaC(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “carbonyl,” refers to a —C(O)— group.

“Halo,” “halogen,” and “halide” include fluorine, chlorine, bromine andiodine.

The term “perhaloalkyl” refers to an alkyl group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkyl groupsinclude, but are not limited to, —CF₃ and —C(CF₃)₃. The term “haloalkyl”refers to an alkyl group where some but not necessarily all of thehydrogen atoms are replaced by halogen atoms. Haloalkyl groups includebut are not limited to —CHF₂ and —CH₂F.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkoxy groupsinclude, but are not limited to, —OCF₃ and —OC(CF₃)₃. The term“haloalkoxy” refers to an alkoxy group where some but not necessarilyall of the hydrogen atoms are replaced by halogen atoms. Haloalkoxygroups include but are not limited to —OCHF₂ and —OCH₂F.

The terms “comprising,” “including,” “having,” “composed of,” areopen-ended terms as used herein, and do not preclude the existence ofadditional elements or components. In a claim element, use of the forms“comprising,” “including,” “having,” or “composed of” means thatwhatever element is comprised, had, included, or composes is notnecessarily the only element encompassed by the subject of the clausethat contains that word.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄₊ or the cationsof various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic,2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Examples of pharmaceuticallyunacceptable acid addition salts include, for example, perchlorates andtetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula I compounds, for example intheir purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula I by reacting, for example, the appropriate acid or base withthe compound according to Formula I. The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patient's body, such as enzymes,to the active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.

“Isotopes” are well known in the art and refer to atoms with the samenumber of protons but different number of neutrons. For example, carbon12, the most common form of carbon, has six protons and six neutrons,whereas carbon 14 has six protons and eight neutrons.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

The GLP-1 compounds, their pharmaceutically acceptable salts orhydrolyzable esters of the present invention may be combined with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions useful for treating the biological conditions or disordersnoted herein in mammalian species, and more preferably, in humans. Theparticular carrier employed in these pharmaceutical compositions mayvary depending upon the type of administration desired (e.g.,intravenous, oral, topical, suppository, or parenteral).

In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like can be employed.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anotherGLP-1 agonist or another type of therapeutic agent or second medicament,or both. Non-limiting examples of the GLP-1 receptor agonists includeexenatide, liraglutide, taspoglutide, albiglutide, lixisenatide, andmixtures thereof.

In one embodiment, the GLP-1 agonist is exenatide (Byetta®) or ByettaLAR®. Exenatide is described, for example, in U.S. Pat. Nos. 5,424,286;6,902,744; 7,297,761, and others, the contents of each of which isherein incorporated by reference in its entirety.

In one embodiment, the GLP-1 agonist is liraglutide(VICTOZA®) (alsocalled NN-2211 and [Arg34,Lys26]-(N-epsilon-(gamma-Glu(N-alpha-hexadecanoyl))-GLP-1 (7-37)),includes the sequence HAEGTFTSDVSSYLEGQAAKEFIAWKVRGRG and is availablefrom Novo Nordisk (Denmark) or Scios (Fremont, Calif. USA). See, e.g.,Elbrond et al., 2002, Diabetes Care. August; 25(8):1398404; Agerso etal., 2002, Diabetologia. February; 45(2):195-202).

In one embodiment, the GLP-1 agonist is taspoglutide (CAS Registry No.275371-94-3) and is available from Hoffman La-Roche. See, for example,U.S. Pat. No. 7,368,427, the contents of which are herein incorporatedby reference in its entirety.

In one embodiment, the GLP-1 agonist isalbiglutide (SYNCRIA® fromGlaxoSmithKline).

In another embodiment, the GLP-1 agonist is lixisenatide (Lyxumia® fromSanofi-Aventis/Zealand Pharma).

Non-limiting examples of the second medicaments are as disclosed above.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various such embodiments, the second medicamentis a DPPIV inhibitor. In various such embodiments, the second medicamentis medically indicated for the treatment of type II diabetes. In varioussuch embodiments, the second medicament is a biguanide, a sulfonylurea,a meglitinide, a thiazolidinedione, an α-glucosidase inhibitor, a bileacid sequestrant, and/or a dopamine-2 agonist.

In another embodiment, the second medicament is metformin.

In another embodiment, the second medicament is sitagliptin.

As set forth herein, compounds of the invention include stereoisomers,tautomers, solvates, hydrates, salts including pharmaceuticallyacceptable salts, and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g., as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, incorporated by reference herein. The compositions canappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substancespreserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment, the oral route being preferred.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid solubility or serveas preservatives can also be included. Furthermore, injectablesuspensions can also be prepared, in which case appropriate liquidcarriers, suspending agents and the like can be employed.

For topical administration, the compounds of the present invention canbe formulated using bland, moisturizing bases such as ointments orcreams.

If a solid carrier is used for oral administration, the preparation canbe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation can be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention, dissolved or suspended in a liquid carrier, preferably anaqueous carrier, for aerosol application. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

An embodiment of the invention also encompasses prodrugs of a compoundof the invention which on administration undergo chemical conversion bymetabolic or other physiological processes before becoming activepharmacological substances. Conversion by metabolic or otherphysiological processes includes without limitation enzymatic (e.g.,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design ofProdrugs,ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

The compounds of the invention can be used therapeutically incombination with i) one or more other GLP-1 modulators and/or ii) one ormore other types of therapeutic agents or second medicaments which canbe administered orally in the same dosage form, in a separate oraldosage form (e.g., sequentially or non-sequentially) or by injectiontogether or separately (e.g., sequentially or non-sequentially).Examples of combination therapeutic agents include Metformin,Sitagliptin (MK-0431, Januvia) an oral antihyperglycemic (antidiabeticdrug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class andExenatide (Byetta) an incretin mimetic. In other embodiments, the secondmedicament is a biguanide such as metformin, a sulfonylurea such asglibenclamide, glipizide, gliclazide, and glimepiride, a meglitinidesuch as repaglinide and nateglinide, a thiazolidinedione such aspioglitazone and rosiglitazone, an α-glucosidase inhibitor such asacarbose and miglitol, a bile acid sequestrant such as colesevelam,and/or a dopamine-2 agonist such as bromocriptine.

Combinations of the invention include mixtures of compounds from i) andii) in a single formulation and compounds from i) and ii) as separateformulations. Some combinations of the invention can be packaged asseparate formulations in a kit. In some embodiments, two or morecompounds from ii) are formulated together while a compound of theinvention is formulated separately.

The dosages and formulations for the other agents to be employed, whereapplicable, will be as set out in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

In certain embodiments, the present invention encompasses compounds thatbind with high affinity and specificity to the GLP-1 receptor in anagonist manner or as an activator or a potentiator. In certainembodiments a compound of the invention acts as a positive allostericmodulator of GLP-1 receptor.

In certain embodiments, the present invention provides a method foractivating, potentiating, or agonizing (i.e., to have an agonic effect,to act as an agonist) a GLP-1 receptor, with a compound of theinvention. The method involves contacting the receptor with a suitableconcentration of an inventive compound to bring about activation of thereceptor. The contacting can take place in vitro, for example incarrying out an assay to determine the GLP-1 receptor activationactivity of an inventive compound undergoing experimentation related toa submission for regulatory approval.

In certain embodiments, the method for activating a GLP-1 receptor, canalso be carried out in vivo, that is, within the living body of amammal, such as a human patient or a test animal. The inventive compoundcan be supplied to the living organism via one of the routes asdescribed above, e.g., orally, or can be provided locally within thebody tissues. In the presence of the inventive compound, activation ofthe receptor takes place, and the effect thereof can be studied.

An embodiment of the present invention provides a method of treatment ofa malcondition in a patient for which activation of an GLP-1 receptor ismedically indicated, wherein the patient is administered the inventivecompound in a dosage, at a frequency, and for a duration to produce abeneficial effect on the patient. The inventive compound can beadministered by any suitable means, examples of which are describedabove.

In certain embodiments, the present invention is directed to compoundsadapted to act as modulators or potentiators of Class B GPCRs. Thesecompounds may have activity on their own or in the presence of receptorligands. Receptors include incretin peptides including GLP-1(7-36) andGLP-1(9-36).

Methods of treatments provided by the invention include administrationof a compound of the invention, alone or in combination with anotherpharmacologically active agent or second medicament to a subject orpatient having a malcondition for which activation, potentiation oragonism of a glucagon-like peptide 1 receptor is medically indicatedsuch as type I diabetes, type II diabetes, gestational diabetes,obesity, excessive appetite, insufficient satiety, or metabolicdisorder.

General Synthetic Methods for Preparing Compounds

Molecular embodiments of the present invention can be synthesized usingstandard synthetic techniques known to those of skill in the art.Compounds of the present invention can be synthesized using the generalsynthetic procedures set forth in Schemes 1-37.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i) If Z═CO then        amide coupling with acid chloride: DIEA, DCM or amide coupling        with acid: EDC, HOBt, DMF or HATU, DMF; If Z═SO₂, then coupling        with sulfonyl chloride: DIEA or NEt₃, DCM or DMF; (ii)        Deprotection of PG₁ e.g., methyl ester deprotection: LiOH,        dioxane, water.

The other enantiomer can be prepared in a similar manner using Scheme 1.

-   -   Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) NH₂OH HCl, TEA,        EtOH.

-   -   Reagents: PG is a protecting group; (i) EDC, HOBt, DMF then        heat; (ii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 3.

-   -   Reagents: PG is a protecting group; (i)NH₂OH, TEA, water or        EtOH; (ii) EDC, HOBt, DMF then heat; (iii) Deprotection e.g.,        methyl ester deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 4.

-   -   Reagents: X₁═O or S; (i)N-Methylmorpholine, isobutyl        chloroformate, THF, DMF; (ii) For X₁=oxygen, then        2-Chloro-1,3-dimethylimidazolinium chloride, TEA, DCM; For        X₁=sulfur then        2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane        2,4-disulfide, THF; (iii) Deprotection e.g., methyl ester        deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 5.

-   -   Reagents: PG is a protecting group and X_(A) and X_(B) are CR₄        or N; (i) For Z═CO, then amide coupling with acid chloride:        DIEA, DCM or amide coupling with acid: EDC, HOBt, DMF or HATU,        DMF; For Z═SO₂, then coupling with sulfonyl chloride DIEA or        NEt₃, DCM or DMF(ii) DIEA,        1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl) sulfonyl)        methanesulfonamide, DCM; (iii) KOAc, bis-pinacolatoborane,        PdCl₂(dppf) or Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (iv)        Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (v) Pd(dppf)Cl₂, Na₂CO₃,        THF, ACN, water; (vi) Deprotection e.g., methyl ester        deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 6.

-   -   Reagents: PG is a protecting group and X_(A) and X_(B) are CR₄        or N; (i) Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (ii)        Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (iii) Deprotection e.g.,        methyl ester deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 7.

-   -   Reagents: PG is a protecting group; (i) DIEA or TEA,        acetonitrile; (ii) Acetamide, boron trifluoride etherate,        DCM; (iii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 8.

-   -   Reagents: PG is a protecting group; (i) Boron trifluoride        etherate, acetamide, DCM; (ii) Zn, I₂, Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (iii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 9.

-   -   Reagents: PG is a protecting group; (i) Pd(dppf)Cl₂, Na₂CO₃,        THF, ACN, water; (ii) Deprotection e.g., methyl ester        deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme10.

-   -   Reagents: PG is a protecting group; (i) Pd(dppf)Cl₂, Na₂CO₃,        THF, ACN, water; (ii) Deprotection e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme11.

-   -   Reagents: PG, PG₂, and PG₃ are protecting groups; (i) Zn, I₂,        Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (ii) Deprotection of PG₂ e.g., tert-butyl carbonate and        PG₃, e.g., SEM deprotection: DCM, TFA; (iii) If Z═CO then        coupling with acid: base (DIEA, TEA, or NMM), coupling reagents        (EDC, HOBt or DCC, HOBt, or DCC, DMAP or HATU), solvent (DMF or        DCM); If Z═SO₂ then coupling with sulfonyl chloride: DIEA or        TEA, DCM or DMF; (iv) Deprotection of PG, e.g., tert-butyl ester        deprotection: DCM, TFA

The other enantiomer can be prepared in a similar manner using Scheme12.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i)        2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane        2,4-disulfide, DME, THF; (ii) isopropanol; (iii) Zn, I₂,        Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (iv) Deprotection of PG₂, e.g., tert-butyl ester        deprotection: DCM, TFA; (v) If Z═CO then coupling with acid:        base (DIEA, TEA, or NMM), coupling reagents (EDC, HOBt or DCC,        HOBt, or DCC, DMAP or HATU), solvent (DMF or DCM); If Z═SO₂ then        coupling with sulfonyl chloride: DIEA or TEA, DCM or DMF; (vi)        Deprotection of PG₁, e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme13.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i) Zn, I₂,        Pd₂(dba)₃, dicyclohexyl(2′,6′-dimethoxy-[1,        1′-biphenyl]-2-yl)phosphine, DMF; (ii) Deprotection of PG₂,        e.g., tert-butyl carbonate deprotection: DCM, TFA; (iii) If Z═CO        then coupling with acid: base (DIEA, TEA, or NMM), coupling        reagents (EDC, HOBt or DCC, HOBt, or DCC, DMAP or HATU), solvent        (DMF or DCM); If Z═SO₂ then coupling with sulfonyl chloride:        DIEA or TEA, DCM or DMF; (iv) Deprotection of PG₁, e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme14.

-   -   Reagents: PG₁ and PG₂ are a protecting group; (i)        1,1,3,3-tetramethylguanidine, THF; (ii) H₂, Dioxane; (iii)        Deprotection of PG₁ e.g., boc-amine deprotection: DCM, TFA; (iv)        If Z═CO then coupling with acid: base (DIEA, TEA, or NMM),        coupling reagents (EDC, HOBt or DCC, HOBt, or DCC, DMAP or        HATU), solvent (DMF or DCM); If Z═SO₂ then coupling with        sulfonyl chloride: DIEA or TEA, DCM or DMF; (v) Deprotection of        PG₂, e.g., tert-butyl ester deprotection: DCM, TFA.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i)        1,1,3,3-tetramethylguanidine, THF; (ii) H₂, Dioxane; (iii)        Deprotection of PG₁ e.g., boc amine deprotection: DCM, TFA; (iv)        If Z═CO then coupling with acid: base (DIEA, TEA, or NMM),        coupling reagents (EDC, HOBt or DCC, HOBt, or DCC, DMAP or        HATU), solvent (DMF or DCM); If Z═SO₂ then coupling with        sulfonyl chloride: DIEA or TEA, DCM or DMF; (v) Deprotection of        PG₂, e.g., tert-butyl ester deprotection: DCM, TFA.

-   -   Reagents: PG is a protecting group; (i)        3-bromo-5-chloro-1,2,4-thiadiazole, NaHCO₃, Pd(dppf)Cl₂, water        and THF, ACN or dioxane; (ii) NaHCO₃, Pd(dppf)Cl₂, water and        THF, ACN or dioxane; (iii) Deprotection of PG, e.g., tert-butyl        ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme17.

-   -   Reagents: PG is a protecting group; (i) NaO^(t)Bu or Cs₂CO₃,        Pd(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Deprotection of PG, e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme18.

-   -   Reagents: PG is a protecting group; (i) NaO^(t)Bu or Cs₂CO₃,        Pd(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Deprotection of PG, e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme19.

-   -   Reagents: PG is a protecting group; (i) (a) where R₂ is        NH—(CR_(a)R_(b))_(m)—COOH: NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU,        DMF then deprotection e.g., tert-butyl ester deprotection: DCM,        TFA; (b) where R₂ is NH—SO₂—R: R₈SO₂NH₂, DCC, DMAP, DCM (c)        where R₂ is NR₄₁R₄₂: HNR₄₁R₄₂, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA; (d) where R₂ is        N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)— heterocyclyl:        HN(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, HATU, DMF then        deprotection e.g., tert-butyl ester deprotection: DCM, TFA; (e)        where R₂ is-N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₇):        NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA then HN(R₁)(R₇), HATU,        DMAP, DCM (f) where R₂ is N(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl:        HN(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl, HATU, DMF then        deprotection e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer and diastereoisomer can be prepared in a similarmanner using Scheme 20.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i) DIEA,        1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide,        DCM; (ii) KOAc, bi s-pinacolatoborane, PdCl₂(dppf); (iii)        Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (iv) Pd(dppf)Cl₂, Na₂CO₃,        THF, ACN, water; (v) Deprotection of PG₂, e.g. CBZ: Pd/C, H₂,        EA; (vi) If Z═CO then amide coupling with acid chloride: DIEA,        DCM or amide coupling with acid: EDC, HOBt, DMF or HATU, DMF; If        Z═SO₂, then coupling with sulfonyl chloride: DIEA or NEt₃, DCM        or DMF; (vii) Deprotection of PG₁, e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme21.

-   -   Reagents: PG is a protecting group; (i) Pd(dppf)Cl₂, Na₂CO₃,        THF, ACN, water; (ii) Deprotection of PG, e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme22.

-   -   Reagents: PG is a protecting group; (i) Zn(CN)₂, Pd(Ph₃)₄,        NMP; (ii) hydroxylamine, NEt₃, EtOH; (iii) EDC, HOBt, DMF then        heat; (iv) Deprotection of PG, e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme23.

-   -   Reagents: PG is a protecting group; (i) NH₄Cl, NaN₃, DMF; (ii)        CsCO₃, or K₂CO₃, DMF, acetone or acetonitrile; (iii)        Deprotection of PG, e.g., tert-butyl ester deprotection: DCM,        TFA.

The other enantiomer can be prepared in a similar manner using Scheme24.

-   -   Reagents: PG is a protecting group; (i) sodium tert-butoxide,        Pd₂(dba)₃, dioxane; (ii) Deprotection of PG, e.g., tert-butyl        ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme25.

-   -   Reagents: PG is a protecting group; (i) NaO^(t)Bu or Cs₂CO₃,        Pd₂(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Pd/C, H₂, EtOH, (iii) Deprotection        of PG, e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme26.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i) HATU, DMF,        DIEA; (ii) Deprotection of PG₂, e.g. benzyl ester deprotection:        Pd/C, H₂, MeOH; (iii) HNR₄₁R₄₂, HATU, DMF; (iv) Deprotection of        PG₁, e.g., tert-butyl ester deprotection: dioxane, HCl or DCM,        TFA.

The other enantiomer and diastereomers can be prepared in a similarmanner using Scheme 27.

-   -   Reagents: PG₁ and PG₂ are protecting groups and X_(A) and X_(B)        are CR₄ or N; (i) Deprotection of PG₁, e.g., tert-butyl ester        deprotection: DCM, TFA; (ii) HATU, DIEA, DMF.

The other enantiomer can be prepared in a similar manner using Scheme28.

-   -   Reagents: PG₁ and PG₂ are protecting groups and X_(A) and X_(B)        are CR₄ or N; (i) Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (ii)        Br—(CR_(a)R_(b))_(m)—R₇, K₂CO₃, DMF; (iii) Deprotection of PG₂,        e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme29.

Reagents: PG₁ and PG₂ are protecting groups and X_(A) and X_(B) are CR₄or N; (i) Pd(dppf)Cl₂, Na₂CO₃, THF, acetonitrile, water; (ii)Deprotection of PG₂, e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme30.

Reagents: PG₁ and PG₂ are protecting groups and X_(A) and X_(B) are CR₄or N; (i) Pd₂(dba)₃,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, NaOtBu, dioxane;(ii) Deprotection of PG₂, e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme31.

-   -   Reagents: PG₁ and PG₂ are protecting groups and X_(A) and X_(B)        are CR₄ or N; (i) Lithium formate, DIEA, Ac₂O, DMF, then        PdCl₂(dppf); (ii) HOBt, EDC, DMF, EtOH; (iii) Deprotection of        PG₂, e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme32.

-   -   Reagents: PG is a protecting group and X_(A) and X_(B) are CR₄        or N; (i) Br—(CR_(a)R_(b))_(m)—R₇, K₂CO₃, DMF; (ii) Pd(dppf)Cl₂,        Na₂CO₃, THF, ACN, water; (iii) Deprotection of PG, e.g.,        tert-butyl ester deprotection: DCM, TFA; (iv) (a) where R₂ is        NH—(CR_(a)R_(b))_(m)COOH: NH₂—(CR_(a)R_(b))_(m)COOPG, HATU, DMF        then NR₄₁R₄₂:NR₄₁R₄₂, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme33.

-   -   Reagents: PG₁, PG₂ and PG₃ are protecting groups; (i) DIEA,        1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide,        DCM; (ii) KOAc, bis-pinacolatoborane, PdCl₂(dppf); (iii)        Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (iv) Pd(dppf)Cl₂, Na₂CO₃,        THF, ACN, water; (v) Deprotection of PG₁, e.g., tert-butyl ester        deprotection: DCM, TFA; (vi) (i) (a) where R₂ is        NH—(CR_(a)R_(b))_(m)—COOH: NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU,        DMF then deprotection e.g., tert-butyl ester deprotection: DCM,        TFA; (b) where R₂ is NH—SO₂—R: R₈SO₂NH₂, DCC, DMAP, DCM (c)        where R₂ is NR₄₁R₄₂: HNR₄₁R₄₂, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA: (d) where R₂ is        N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl:        HN(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, HATU, DMF then        deprotection e.g., tert-butyl ester deprotection: DCM, TFA; (e)        where R₂ is —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₇):        NH₂—(CR_(a)R_(b))_(m)—COOPG₃, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA then HN(R₁)(R₇), HATU,        DMAP, DCM (f) where R₂ is N(R₁)-heterocyclyl:        HN(R₁)-heterocyclyl, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA. (vii) Deprotection of        PG₂, e.g. CBZ: Pd/C, H₂, EA; (viii) If Z═CO then amide coupling        with acid chloride: DIEA, DCM or amide coupling with acid: EDC,        HOBt, DMF or HATU, DMF; If Z═SO₂, then coupling with sulfonyl        chloride: DIEA or NEt₃, DCM or DMF; (ix) Deprotection of PG₃,        e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme34.

-   -   Reagents: PG₁ and PG₂ are protecting groups; (i) HATU, DMF,        DIEA; (ii) Deprotection of PG₁, e.g., tert-butyl ester        deprotection: dioxane, HCl or DCM, TFA; (iii) HNR₄₁R₄₂, HATU,        DMF; (iv) Deprotection of PG₂ e.g. benzyl ester deprotection:        Pd/C, H₂, MeOH.

The other enantiomer and diastereomers can be prepared in a similarmanner using Scheme 35.

-   -   Reagents: PG is a protecting group; (i) (a) where R₂ is        NH—(CR_(a)R_(b))_(m)—COOH: NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU,        DMF then deprotection e.g., tert-butyl ester deprotection: DCM,        TFA; (b) where R₂ is NH₂-heterocyclyl, NH—SO₂—R₈: R₈SO₂NH₂, DCC        or EDC, DMAP, DCM (c) where R₂ is NR₄₁R₄₂: HNR₄₁R₄₂, HATU, DMF        then deprotection e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer and diastereoisomers can be prepared in a similarmanner using Scheme 36.

-   -   Reagents: PG is a protecting group; (i) (a) where R₂ is        NH—(CR_(a)R_(b))_(m)—COOH: NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU,        DMF then deprotection e.g., tert-butyl ester deprotection: DCM,        TFA; (b) where R₂ is NH—SO₂—R₈: R₈SO₂NH₂, DCC, DMAP, DCM (c)        where R₂ is NR₄₁R₄₂: HNR₄₁R₄₂, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer and diastereoisomers can be prepared in a similarmanner using Scheme 37.

-   -   Reagents: PG₁, and PG₂ are protecting groups and X_(A) and X_(B)        are CR₄ or N; (i) Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (ii)        Pd(dppf)Cl₂, Na₂CO₃, THF, ACN, water; (iii) Deprotection of PG₂,        e.g. CBZ: Pd/C, H₂, EA; (iv) If Z═CO then amide coupling with        acid chloride: DIEA, DCM or amide coupling with acid: EDC, HOBt,        DMF or HATU, DMF; If Z═SO₂, then coupling with sulfonyl        chloride: DIEA or NEt₃, DCM or DMF; (v) Deprotection of PG₁,        e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme38.

-   -   Reagents: (i) HATU, DMF; (ii) hydrazine hydrate, THF,        EtOH; (iii) thiocarbonyldiimadazole, DIEA, THF.

The other enantiomer and diastereoisomers can be prepared in a similarmanner using Scheme 39.

Examples

The invention is further illustrated by the following examples. Theexamples below are non-limiting are merely representative of variousaspects of the invention.

General Methods NMR Spectra

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were obtained in solution ofdeuteriochloroform (CDCl₃) or dimethyl sulfoxide (d₆-DMSO). NMR spectrawere processed using MestReNova 6.0.3-5604.

LCMS Data

Mass spectra (LCMS) were obtained using one of 6 systems. System 1a:Agilent 1100/6110 HPLC system equipped with a Thompson ODS-A, 100 A, 5μ(50×4.6 mm) column using water with 0.1% formic acid as the mobile phaseA, acetonitrile with 0.1% formic acid as the mobile phase B, water with5 mM ammonium acetate as the mobile phase C, and acetonitrile with 5 mMammonium acetate as the mobile phase D with a flow rate of 1 mL/min.Method 1: 20-100% mobile phase B (80-0% A) over 2.5 min then held at100% B for 2.5 min. Method 2: 5% mobile phase B (95% A) for 1 min, 5-95%B over 9 min, then held at 95% B for 5 min. Method 3: 20-100% mobilephase B (80-0% A) over 2.5 min then held at 100% B for 4.5 min. Method12: 5% D (95% C) for 1 min. then 5-95% D over 9 min. and held at 95% Dfor 5 min. System Ib: Agilent 1100/6110 HPLC system equipped with aAgilent Poroshell 120 EC-C8, 2.7μ (50×3 mm) column using water with 5 mMammonium acetate as the mobile phase C, and acetonitrile with 5 mMammonium acetate as the mobile phase D with a flow rate of 1 mL/min.Method 13: 5% D (95% C) to 95% D over 12 min. then held at 95% D for 2.8min. and to 5% D over 0.2 min. System 1c: Agilent 1100/6110 HPLC systemequipped with a Agilent Poroshell 120 EC-C18, 2.7μ (50×3 mm) columnusing water with 5 mM ammonium acetate as the mobile phase C, andacetonitrile with 5 mM ammonium acetate as the mobile phase D with aflow rate of 1 mL/min. Method 14: 5% D (95% C) to 95% D over 12 min.then held at 95% D for 2.8 min. and then to 5% D over 0.2 min. Method15: 20% D (80% C) to 95% D over 3 min. and hold at 95% D 1.8 min. thento 20% D over 0.2 min. Method 16: 20% D (80% C) to 95% D over 3.0 min.and hold at 95% D for 3.8 min. then 20% D over 0.2 min. System 2:Agilent 1200 LCMS equipped with an Agilent Zorbax Extend RRHT 1.8 μm(4.6×30 mm) column using water with 0.1% formic acid as mobile phase Aand acetonitrile with 0.1% formic acid as mobile phase B. Method 4:5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, thenheld at 95% for 0.5 min with a flow rate of 4.5 mL/min. Method 5: 5-95%mobile phase B over 14 min with a flow rate of 2.5 mL/min, then held at95% for 0.5 min with a flow rate of 4.5 mL/min. System 3: WatersFractionlynx LCMS system equipped with an Agilent Zorbax Extend RRHT 1.8μm, (4.6×30 mm) column using water with 0.1% formic acid as mobile phaseA and acetonitrile with 0.1% formic acid as mobile phase B. Method 6:5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, thenheld at 95% for 0.5 min with a flow rate of 4.5 mL/min. Method 7: 5-95%mobile phase B over 14 min with a flow rate of 2.5 mL/min, then held at95% for 0.5 min with a flow rate of 4.5 mL/min. System 4: Agilent 1260LCMS equipped with an Agilent Zorbax Extend RRHT 1.8 μm (4.6×30 mm)column using water with 0.1% formic acid as mobile phase A andacetonitrile with 0.1% formic acid as mobile phase B. Method 8: 5-95%mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, then held at95% for 0.5 min with a flow rate of 4.5 mL/min. Method 9: 5-95% mobilephase B over 14 min with a flow rate of 2.5 mL/min, then held at 95% for0.5 min with a flow rate of 4.5 mL/min. System 5: Agilent 1260 LCMSequipped with a Waters Xselect CSH C18 3.5 μm (4.6×50 mm) column usingwater with 0.1% formic acid as mobile phase A and acetonitrile with 0.1%formic acid as mobile phase B. Method 10: The gradient was 5-95% mobilephase B over 13.0 min with a flow rate of 2.5 mL/min, then held at 95%for 1.0 min with a flow rate of 4.5 mL/min. Method 11: The gradient was5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, thenheld at 95% for 0.6 min with an flow rate of 4.5 mL/min. System 6:Waters Acquity UPLC system equipped with a Acquity UPLC BEH C18, 1.7 μm(2.1×50 mm) or Phenomenex Kinetex C18, 1.7 μm (2.1×50 mm) column usingwater with 10 mM ammonium formate as mobile phase A, acetonitrile asmobile phase B with a flow rate of 0.5 mL/min. Method 17: 10% mobilephase B (90% A) for 0.5 min, 10-95% B over 3 min, then held at 95% B for1.1 min, 95-10% B over 0.1 min then held for 0.3 min and the total runtime is 5 min. Method 18: 20% mobile phase B (80% A) for 0.5 min, 20-95%B over 3 min, then held at 95% B for 1.1 min, 95-20% B over 0.1 min,then held for 0.3 min and the total run time is 5 min. Method 19: 30%mobile phase B (70% A) for 0.5 min, 30-95% B over 2.2 min, then held at95% B for 1.9 min, 95-30% B over 0.1 min, then held for 0.3 min and thetotal run time is 5 min. Method 20: 40% mobile phase B (60% A) for 0.5min, 40-95% B over 1.9 min, then held at 95% B for 2.2 min, 95-40% Bover 0.1 min, then held for 0.3 min and the total run time is 5 min.Method 21: 20% mobile phase B (80% A) for 0.5 min, 20-95% B over 2.7min, then held at 95% B for 1.4 min, 95-20% B over 0.1 min, then heldfor 0.3 min and the total run time is 5 min. Method 22: 40% mobile phaseB (60% A) for 0.5 min, 40-95% B over 1.6 min, then held at 95% B for 2.5min, 95-40% B over 0.1 min, then held for 0.3 min and the total run timeis 5 min.

Hydrogenations

Hydrogenation reactions were performed using a Thales NanotechnologyH-Cube reactor equipped with the specified CatCart or using standardlaboratory techniques.

Reaction Conditions and Abbreviations

Pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene usedin the procedures were from Aldrich Sure-Seal bottles or Acros AcroSealdry solvent and kept under nitrogen (N₂). All reactions were stirredmagnetically and temperatures are external reaction temperatures. Thefollowing abbreviations are used: ethyl acetate (EA),1-methy-2-pyrrolidinone (NMP), triethylamine (TEA),N-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N,N-dimethylformamide (DMF), dimethylacetamide (DMA), Di-tert-butyl dicarbonate (Boc₂O),N,N-Diisopropylethylamine (DIEA), acetic acid (AcOH), hydrochloric acid(HCl), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), tert-butanol(t-BuOH), sodium hydride (NaH), sodium triacetoxyborohydride(Na(OAc)₃BH), ethanol (EtOH), methanol (MeOH), acetonitrile (ACN).

Purifications

Chromatographies were carried out using a Combiflash Rf flashpurification system (Teledyne Isco) equipped with Redisep (TeledyneIsco), Telos (Kinesis) or Grace Resolv (Grace Davison DiscoverySciences) silica gel (SiO₂) columns. Preparative HPLC purifications wereperformed using one or two systems. System 1: Varian ProStar/PrepStarsystem equipped with a Waters SunFire Prep C18 OBD, 5 μm (19×150 mm)column using water containing 0.05% trifluoroacetic acid as mobile phaseA, and acetonitrile with 0.05% trifluoroacetic acid as mobile phase B.The gradient was 40-95% mobile phase B over 10 min, held at 95% for 5-10min, and then return to 40% over 2 min with flow rate of 18 mL/min.Fractions were collected using a Varian Prostar fraction collector by UVdetection at 254 nm and were evaporated using a Savant SpeedVac Plusvacuum pump or a Genevac EZ-2. System 2: Waters Fractionlynx systemequipped with an Agilent Prep-C18, 5 μm (21.2×50 mm) column using watercontaining 0.1% formic acid as mobile phase A, and acetonitrile with0.1% formic acid as mobile phase B. The gradient was 45-95% mobile phaseB over 7.5 min, held at 95% for 1 min, and then returned to 45% over 1.5min with a flow rate of 28 mL/min. Fractions were collected by UVdetection at 254 nm or by mass and evaporated using a Genevac EZ-2.

Chiral Methods

Chiral Method:

Enantiomeric excess was determined by integration of peaks that wereseparated on a Diacel Chiralpak IA, 4.6×250 mm column, 5 μm particlesize. The solvents used were “Solvent A”: 4:1 (hexanes with 0.2% TFA):DCM, and “Solvent B”: EtOH. The flow rate was held at 1.0 mL/min withthe following gradient: Increase Solvent B from 2-10% over 30 min, holdSolvent B at 10% for 15 min.

Chiral Method 2:

Enantiomeric excess was determined by integration of peaks that wereseparated on a Daicel Chiralpak IC, 4.6×250 mm column, 5 μm particlesize running an isocratic mixture of 76% (0.2% TFA in iso-hexanes), 19%DCM and 5% EtOH at a flow rate of 1.5 mL/min.

Chiral Preparative HPLC:

This was carried out using a Gilson preparative HPLC system equippedwith a Daicel Chiralpak IC column, 20×250 mm column, 5 μm particle sizerunning an isocratic mixture of mobile phase A (60% (0.2% TFA iniso-hexanes) and 40% DCM) at 15 mL/min and at-column-dilution withmobile phase B (EtOH) at 1.5 mL/min. Fractions were collected by UVdetection at 254 nm and evaporated using a Genevac EZ-2.

Experimental Procedures General Procedures General Procedure 1:Preparation of Nitriles.

A stirred a solution of bromide or triflate (1 eq), zinc cyanide (2 eq)and tetrakis (triphenylphosphine) palladium (1-5 mol %) in dry NMP(0.5-1 M) was degassed with N₂. The reaction was heated to 100° C. for18 h while stirring under N₂. The reaction mixture was cooled and pouredinto water and DCM. The solid material was removed by filtration and thefiltrate was extracted with water. The organic layer was dried overMgSO₄ and concentrated. The crude product was purified bychromatography.

General Procedure 2: Preparation of Amidoximes.

To a stirring solution of nitrile (1 eq) in EtOH was added hydroxylamine(50% solution in H₂O, 5 eq) and TEA (1.1 eq). The mixture was heated for2-12 h at 80-85° C. then concentrated. The resulting solid was dissolvedin EA, washed with water, then dried with Na₂SO₄, concentrated and usedwithout further purification. Alternatively, to a stirring solution ofnitrile (1 eq) and TEA (2-3 eq) in DMF or EtOH was added hydroxylaminehydrochloride (2-3 eq). The mixture was stirred at room temperature upto 80° C. for up to 24 h then concentrated. The resulting solid wasdissolved in EA or DCM, washed with water or brine, then dried withNa₂SO₄, concentrated, and used without further purification.

General Procedure 3: Preparation of Amides via Acid Chlorides.

To a solution of amine (1 eq) and base (either DIEA or TEA) (2-3 eq) inDCM (0.06-0.30 M) was treated with the appropriate acid chloride(1.0-1.5 eq). The reaction mixture was stirred until the reaction wascomplete. The reaction was diluted with DCM and washed with saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and concentrated.The product was purified by chromatography. Alternatively, the crudereaction mixture can be carried on to the next step without furtherpurification.

General Procedure 4: Hydrolysis of Esters to Acids.

To a stirring solution of ester (1 eq) in THF or dioxane and water, wasadded NaOH or LiOH (1-3 eq). The reaction mixture was stirred at up to60° C. for up to 18 h. The reaction mixture was neutralized with AcOH orHCl and either diluted with water or concentrated. If the reactionmixture was diluted with water, then HCl was added to acidify thereaction mixture to a pH of approximately 2. The resulting precipitatewas isolated by filtration to yield product which can be purified bychromatography, preparative HPLC, or used without purification. If thereaction mixture was concentrated, the crude material was diluted withDCM or EA and washed with brine. The organic layer was concentrated andpurified by chromatography or preparative HPLC to give final product.Alternatively, the crude material can be carried forward withoutpurification.

General Procedure 5: Preparation of Oxadiazoles Via Acids or AcidChlorides. Oxadiazoles Via Acids:

To a solution of acid (1 eq) in DMF was added HOBt (2 eq) and EDC (2eq). After stirring for 2 h, amidoxime (2 eq) was added and the mixturewas stirred at room temperature for up to 12 h. The reaction mixture wasthen heated to 100° C. for up to 12 h. Alternatively, after stirring atroom temperature, the reaction mixture was diluted with DCM, washed withNaHCO₃, then dried with Na₂SO₄ and concentrated. The resulting residuewas dissolved in EtOH and heated in a microwave for 35 min at 110° C.The solvent was removed and the final product was purified bypreparative HPLC.

Oxadiazoles via Acid Chlorides: To synthesize oxadiazoles via acidchlorides, dioxanes and DIEA (1.5 eq) were added to a stirred solutionof amidoxime (1 eq) followed by an acid chloride (1.1 eq). The reactionmixture was stirred at room temperature for 30 min then at 120° C. forup to 6 h. The reaction mixture was allowed to cool to room temperature,diluted with EA and washed with brine. The organics were concentratedand the residue purified by chromatography.

General Procedure 6: Removal of Tert-Butyl Carbamate.

A solution of the tert-butyl carbamate (1 eq) in DCM (0.06 M) wastreated with TFA (0.16-0.33 M) or HCl in ether (0.16-0.33 M). Thereaction mixture was stirred at either room temperature or 30° C. untilcomplete. The solvent was removed and the product was purified bychromatography or preparative HPLC.

General Procedure 7: Preparation of Amides Via Peptide Coupling.

A solution of amine (1.0 eq) and base (DIEA, TEA or NMM) (0-3.0 eq) inDCM or DMF (0.08-0.10 M) was treated with the appropriate carboxylicacid (1.0-1.5 eq). To this mixture was added the coupling reagent. Thecoupling reagent could be HATU (1.05-2.5 eq) optionally with DMAP(0.01-1 eq), EDC (1.5 eq) with HOBt (1.5 eq) or DMAP (0.01-1 eq), DCC(1.1 eq) with HOBt (1.1 eq) or DCC (1.5 eq) with DMAP (2.0 eq). Thereaction mixture was stirred until the reaction was complete. Thereaction was diluted with EA and washed with saturated aqueous NaHCO₃.The organic layer was dried over MgSO₄ and concentrated. The product waspurified by chromatography or alternatively can be carried on to thenext step without further purification.

General Procedure 8: Deprotection of Esters to Acids, Deprotection ofBoc-Amines, and/or Protodesilylation of Protected Alcohols

A solution of the tert-butyl ester or Boc-amine (1.00 eq) in DCM (0.06M) was treated with TFA (0.16-0.33 M) or 1-4N HCl in ether or dioxane(10.0-20.0 eq). The reaction mixture was stirred at either roomtemperature or 30° C. until complete. The solvent was removed and theproduct was purified by chromatography or preparative HPLC. Thisprocedure was also applicable for protodesilylation of tert-butyl,dimethylsilyl protected alcohols.

A solution of the methyl ester (1.00 eq) in dioxane (0.04-0.08 M) wastreated with 1-6N aqueous HCl (10-100 eq). The reaction mixture wasstirred at either room temperature or 30° C. until complete. The solventwas removed and the product was purified by chromatography orpreparative HPLC.

General Procedure 9: Formation of Triflate.

A solution of the phenol (1.0 eq) in DCM (0.25 M) was treated with1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.1 eq). The reaction mixture was stirred at room temperature untilcomplete. The reaction was stirred with water and saturated aqueousNaHCO₃. The organic layers was dried and concentrated. The material waspurified by chromatography or alternatively used without purification.

General Procedure 10: Palladium-Catalyzed Coupling Reactions.

A solution of boronic acid or boronate ester (1.0-1.3 eq), halide(1.0-1.3 eq), sodium bicarbonate or sodium carbonate decahydrate(2.0-2.5 eq), anddichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) orPd(dppf)Cl₂ were combined in THF, acetonitrile, or dioxane (0.1-0.2 M)and water (0.25-0.50 M). The reaction was heated at 80 to 100° C. untilcomplete. The reaction was diluted with EA and washed with saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and concentrated.The product can be purified by chromatography, preparative HPLC, orcarried on to the next step without further purification.

General Procedure 11: Palladium-Catalyzed Aryl Amidation.

A solution of aryl bromide or triflate (1.00 eq), sodium tert-butoxideor cesium carbonate (1-2 eq) and amine (1.0-1.5 eq) in dioxane or THF(0.05M) was degassed using N₂ bubbling for 10 min. Pd₂(dba)₃ (0.10 eq)and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.15 eq) areadded and the reaction mixture was heated for 45-60 min at 100-120° C.in a microwave reactor or up to 80° C. with conventional heating for upto 18 h. The reaction was diluted with EA and washed with saturatedaqueous NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The product can be purified by chromatography, preparativeHPLC, or carried on to the next step without further purification.

General Procedure 12: Alkylation of Phenols, Imidazoles, Lactams andAmines.

To a solution of a phenolic intermediate in DMF, acetone or ACN (0.1 M)were added the appropriate bromoalkane (1.5 eq) or tosylate and eitherCsCO₃ (1.5-2.0 eq) or K₂CO₃ (1.5-2.0 eq). The reaction mixture washeated at 40-70° C. for up to 18 h, then diluted with DCM and washedwith H₂O. The organic layer was dried over Na₂SO₄ and concentrated. Theproduct can be purified by chromatography, preparative HPLC, or carriedon to the next step without further purification.

General Procedure 13: Sulfonate or Sulfonamide Formation.

To a solution of alcohol or amine in DCM (0.02 M) was added the sulfonylchloride (2 eq) and triethylamine (3 eq). The reaction was stirred atroom temperature until complete. The reaction was diluted with DCM andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated. The product can be purified by chromatography,preparative HPLC, or carried on to the next step without furtherpurification.

General Procedure 14: Reduction of Aryl Nitro to an Aryl Amine.

To a stirring solution of aryl nitro (1 eq) in THF purged with N₂ wasadded palladium on carbon. The reaction mixture was subjected to an H₂atmosphere for up to 4 h. The reaction mixture can be filtered over apad of celite and solvent concentrated. The crude material was carriedforward without further purification.

General Procedure 15: Preparation of a Secondary or Tertiary Amine ViaReductive Amination.

To a stirring solution of aldehyde or ketone (0.9-1.0 eq) in DCM or1,2-dichloroethane or THF was added an amine (0.9-1.1 eq). Afterstirring at room temperature for up to 2 h, one drop of acetic acid(optional) was added followed by sodium triacetoxyborohydride (1.5-2.0eq) and the reaction mixture was stirred overnight. In some cases it isnecessary to filter the reaction mixture, redissolve and add additionalreducing agent to drive the reaction to completion. The crude reactionmixture was quenched with NaHCO₃ and stirred for 5 min. The aqueouslayer was extracted with DCM and the organic layer was dried over MgSO₄and concentrated. The final product was isolated by chromatography.

General Procedure 16: Preparation of 2-Iodopyrimidines

To a stirring solution of a 2-chloro pyrimidine (1 eq) in 57% aqueoushydrogen iodide (1 mL) was added sodium iodide (2 eq). The reactionmixture was stirred at ambient temperature until the starting materialwas consumed. The reaction mixture was quenched with NaHCO₃ (5 mL) thenextracted with EA (3×5 mL). The combined organic layer was washed withbrine (10 mL), dried over MgSO₄ and concentrated. The crude product wasused in the subsequent step without purification.

General Procedure 17. Preparation of 2-Iodopyridines

To a stirring solution of a 2-chloropyridine (1 eq) in acetonitrile (2mL) was added sodium iodide (6 eq). The reaction mixture was heated to40° C. and acetyl chloride (0.6 eq) was added. The reaction mixture wasstirred until the staring material was consumed. The reaction wasquenched with NaHCO₃ (5 mL) and extracted with EA (3×5 mL). The combinedorganic layer was washed with brine (10 mL), dried over MgSO₄ andconcentrated. The crude product was used in the subsequent step withoutpurification.

General Procedure 18: Deprotection of Cbz to Amine or Deprotection ofBenzyl Esters to Acids.

Conventional Hydrogenations: To a stirring solution of Cbz-protectedamine or benzyl protected ester (1.0 eq) in EA, THF, EtOH, or MeOH(0.01-0.05 M) was added Pd/C and the reaction was stirred under hydrogenuntil complete. The catalyst was filtered and the solvent was removed.The product was purified by chromatography or alternatively can becarried onto the next step without further purification.

Hydrogenation using H-cube: A solution of Cbz-protected amine or benzylprotected ester (1.0 eq) in dioxane or THF (0.01-0.03 M) was passed overa 10% Pd/C CatCart in a Thales Nanotechnology H-Cube reactor at 1mL/min. The solvent was evaporated and the product was carried to thenext step without further purification.

General Procedure 19: Preparation of Aryl-Acids from Aryl Bromides

To a stirring solution of oven-dried lithium formate (3 eq) and DIEA (2eq) under N₂ in DMF (0.1 M) was added acetic anhydride (2 eq). After 30minutes, the mixture was degassed by N₂ bubbling for 15 min and thenadded to a similarly degassed solution of aryl bromide (1 eq) andPdCl₂(dppf) (0.1 eq) in DMF (0.1 M). The resulting mixture was heated ina microwave reactor for 1 hr at 120° C. After cooling, the mixture wasdiluted with DCM and washed with water. The organic layer was dried(Na₂SO₄) and concentrated. The resulting crude material was purified bychromatography.

General Procedure 20: Alkylation of Phenols Via Mitsunobu Condensationof Alcohols

To a stirring solution of phenol (1 eq) in THF was added an alcohol (1.1eq), triphenyl phosphine (1.1 eq) and diisopropyl azodicarboxylate (1.1eq). The reaction mixture was stirred overnight, concentrated andpurified by preparative HPLC.

General Procedure 21: Palladium Catalyzed Coupling (SonogashiraCoupling)

To a suspension of alkyne (1 eq), iodide (1.2 eq), and diethylamine (5eq) in anhydrous diethyl ether (0.2 M) was added CuI (0.1 eq) followedby Pd(PPh₃)₂Cl₂ (0.05 eq). The reaction mixture was stirred under N₂ atroom temperature for 24 h. The reaction mixture was diluted with ethylacetate, washed with saturated aqueous ammonium chloride then brine, anddried over MgSO₄. The crude product was purified by silica gel columnchromatography.

General Procedure 22: Methyl or Ethyl Ester Formation

To a stirring suspension of amino acid (1 eq) in MeOH or EtOH (0.5 M)was added TMS-C1 (4-10 eq) and the mixture stirred at ambienttemperature (RT-reflux) for 4-24 h. The reaction mixture was cooled andconcentrated/purified to yield desired ester.

General Procedure 23: BOC Protection.

To a stirring suspension of amino ester (1 eq) in DCM (0.25 M) at 0° C.was added DIEA (1.1 eq) and di-tert-butyl dicarbonate (1.2 eq). Thereaction was stirred for between 4-24 h before being washed with waterand dried over MgSO₄. The final product was isolated by chromatography.

General Procedure 24: Swern Oxidation

To a stirring solution of oxalyl chloride (1.6 eq) in DCM (0.17 M) at−78° C. was added DMSO (3.2 eq) and the reaction stirred for 10 mins. Asolution of alcohol (1 eq) in DCM was then added by cannula and thereaction stirred at −78° C. for 2 h before the addition of DIEA (5 eq).The solution was warmed to 0° C., stirred for an additional 60 minutesthen washed with saturated ammonium chloride solution. The organic layerwas dried over MgSO₄ and concentrated. The crude product was purified bycolumn chromatography or used directly

General Procedure 25: Sodium Borohydride Reduction

To a stirring solution of ketone (1 eq) in MeOH (0.17 M) at −78° C. wasadded NaBH₄ (0.7 eq). The reaction was stirred for 30 min before theaddition of saturated ammonium chloride solution and warming to roomtemperature. MeOH was removed by reduced pressure distillation and theaqueous extracted with DCM. The combined organic extracts were driedover MgSO₄ and concentrated. The final product was isolated bychromatography.

General Procedure 26: t-Butyl Ester Formation

To a stirring suspension of acid (1 eq) in DME (0.5 mL) at −10° C. wasadded concentrated sulfuric acid (6 eq) followed by 2-methylprop-1-ene(100 eq). The mixture was sealed in a pressure vessel and stirred at 0°C. for 18 h. The reaction was then cooled to −10° C. and the vesselopened. The reaction was warmed to RT over 30 minutes over which timeall the isobutylene evaporated. The reaction was diluted with EA andsaturated sodium bicarbonate was added to pH 8 with vigorous stirring.The phases were separated and the aqueous re-extracted with EA. Thecombined organic extracts were dried over MgSO₄ and concentrated. Thefinal product was isolated by chromatography.

General Procedure 27: Boronic Acid Synthesis.

To a stirring solution of bromide (1 eq) in THF (0.14 M) at −78° C. wasadded butyllithium (1.5 eq) and the solution stirred for 20 mins.Trimethyl borate (1.1 eq) was added and the reaction warmed to RT. Themixture was quenched with water and extracted with ethyl acetate. Thecombined organics were washed successively with 1 N HCl and saturatedbrine (50 ml), dried over MgSO₄ and concentrated. The final product wasisolated by chromatography.

General Procedure 28. Hydrazide Formation

To a stirring solution of methy ester (1 eq) in 1:1 THF: EtOH (0.05 M)was added hydrazine hydrate (10 eq) and the solution stirred for 16 h.The product was precipitated with water and isolated by filtration.

General Procedure 29: Oxadiazole Thione Formation

To a stirring solution of hydrazide (1 eq) and DIEA in THF (0.027 M) wasadded thiocarbonyldiimidazole (1.2 eq) and the solution stirred for 2 h.The mixture was warmed to 45° C. for a further 1 h then quenched withaqueous AcOH and extracted with DCM. The organics were dried through ahydrophobic frit and concentrated. The final product was isolated bychromatography.

General Procedure 30: Amino Alcohol Synthesis.

To a stirring solution of diisopropylamine (1.15 eq) in THF (0.34 M) at0° C. was added butyllithium (1.1 eq of a 2.4 M solution in hexanes).After 30 mins, the mixture was cooled to −78° C. and treated withtert-butyl 2-((diphenylmethylene)amino)acetate (1 eq). After 30 mins,chlorotrimethylsilane (3 eq) was added and the mixture allowed to warmto room temperature. The resulting solution was added to a stirringsolution of aldehyde (1 eq) and zinc chloride (0.05 eq of a 0.5 Msolution in diethyl ether) in THF (0.36 M). After 16 h, the mixture wasquenched with 10% aqueous citric acid and stirred for a further 16 h.The product was isolated by direct strong-cation-exchange ion-exchangechromatography of the reaction mixture and used without furtherpurification. Synthesis of Representative Compounds4-(heptyloxy)benzonitrile

Prepared using General Procedure 1: A stirred a solution of1-bromo-4-(heptyloxy)benzene (2.0 g, 7.37 mmol), zinc cyanide (1.73 g,14.74 mmol) and tetrakis (triphenylphosphine) palladium (76.12 mg, 0.07mol) in dry NMP (20 mL) was degassed with N₂. The reaction was heated to100° C. for 18 h while stirring under nitrogen. The reaction mixture wascooled and poured into water (100 mL) and DCM (20 mL). The solidmaterial was removed by filtration and the filtrate was extracted withwater (3×20 mL). The organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by chromatography(EA/hexanes) to afford 1.15 g (73%) of 4-(heptyloxy)benzonitrile as alight yellow solid. LCMS-ESI (m/z) calculated for C₁₄H₁₉NO: 217.1; found218.1 [M+H]⁺, t_(R)=11.14 min (Method 2). ¹H NMR (400 MHz, CDCl₃) δ7.64-7.50 (m, 2H), 7.05-6.83 (m, 2H), 3.99 (t, J=6.5 Hz, 2H), 1.89-1.69(m, 2H), 1.58-1.12 (m, 8H), 0.90 (dd, J=9.1, 4.5 Hz, 3H). ¹³C NMR (101MHz CDCl₃) δ 162.47, 133.91, 132.78, 132.12, 129.13, 119.31, 115.18,103.58, 68.41, 31.73, 28.98, 25.89, 22.58, 14.07.

(Z)-4-(heptyloxy)-N′-hydroxybenzimidamide

Prepared using General Procedure 2: To a stirring solution of4-(heptyloxy)benzonitrile (1.0 g, 4.6 mmol) in EtOH (15 mL) were addedhydroxylamine hydrochloride (0.96 g, 13.8 mmol) and TEA (2.22 g, 23.0mmol). The reaction was heated to 85° C. for 2 h. The solvent wasremoved under reduced pressure and the residue was diluted with water(20 mL) and extracted with DCM (3×10 mL). The combined organic layerswere concentrated under reduced pressure. The crude material wascrystallized from isopropanol (20 mL) to afford 1.05 g (91%) of(Z)-4-(heptyloxy)-N′-hydroxybenzimidamide as a white solid. LCMS-ESI(m/z) calculated for C₁₄H₂₂N₂O₂: 250.2; found 251.3 [M+H]⁺, t_(R)=1.70min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 1H), 7.59 (d, J=8.6Hz, 2H), 6.93 (t, J=14.7 Hz, 2H), 5.82-5.48 (m, 2H), 3.97 (t, J=6.5 Hz,2H), 1.83-1.55 (m, 2H), 1.56-1.05 (m, 8H), 0.87 (t, J=6.7 Hz, 3H). ¹³CNMR (101 MHz CDCl₃) δ 159.19, 150.53, 126.64, 125.55, 113.87, 67.40,31.21, 28.62, 28.40, 25.44, 22.02, 13.92.

(S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate

To a solution of (S)-2-amino-3-(4-(tert-butoxycarbonyl)phenyl)propanoicacid (500.0 mg, 1.88 mmol) in MeOH (20 mL) at 0° C. was slowly addedthionyl chloride (447.64 mg, 3.77 mmol). The reaction was stirred for 1h at 0° C. then warmed to room temperature and stirred for 1 h. Thesolvent was removed under reduced pressure. The reaction mixture waswashed with saturated aqueous NaHCO₃ (20 ml) and extracted with DCM(3×10 ml). The organic layer was dried over MgSO₄ and concentrated. Thecrude product was purified by chromatography (EA/hexanes) to afford 425mg (95%) of (S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate as theHCl salt. LCMS-ESI (m/z) calculated for C₁₂H₁₅NO₄: 237.1; found 238.0[M+H]⁺, t_(R)=1.01 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s,3H), 7.94 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.37 (t, J=6.8 Hz,1H), 3.86 (s, 3H), 3.68 (s, 3H), 3.20 (dd, J=11.8, 6.8 Hz, 2H).

(S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate

Prepared using General Procedure 3: To the solution of (S)-methyl4-(2-amino-3-methoxy-3-oxopropyl)benzoate (425.0 mg, 1.79 mmol) in DCM(10 mL) and DIEA (463.0 mg, 3.58 mmol) was added 4-(tert-butyl)benzoylchloride (556.6 mg, 2.83 mmol) at room temperature. The reaction wasstirred for 2 h and the reaction was partitioned between DCM andsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by chromatography(EA/hexanes) to afford 317 mg (45%) of (S)-methyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate. LCMS-ESI(m/z) calculated for C₂₃H₂₇NO₅: 397.2; found 398.1 [M+H]⁺, t_(R)=2.31min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.97-7.75 (m, 2H), 7.67-7.51(m, 2H), 7.46-7.26 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.60 (d, J=7.4 Hz,1H), 5.03 (dt, J=7.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.28 (dd,J=13.7, 5.8 Hz, 1H), 3.18 (dd, J=13.7, 5.5 Hz, 1H), 1.24 (s, 9H).

(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid(INT-1)

Prepared using General Procedure 4: To a stirred solution of (S)-methyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (316.6 mg,0.79 mmol) in dioxane (15 mL) and water (1 mL) at 0° C. was addedlithium hydroxide monohydrate (93.52 mg, 2.23 mmol). After 2 h, thesolution was neutralized with 1 M HCl to pH 7.0. The mixture waspartitioned between DCM (15 mL) and saturated aqueous NaHCO₃ (10 mL).The organic layer was washed with saturated aqueous NaHCO₃ (3×10 mL) andbrine (10 mL). The organic layer was dried over MgSO₄ and concentratedto afford 208 mg (69%) of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid,INT-1. LCMS-ESI (m/z) calculated for C₂₂H₂₅NO₅: 383.2; found 384.1[M+H]⁺, t_(R)=2.13 min. (Method 1). ¹H NMR (400 MHz, DMSO) δ 12.86 (s,1H), 8.80 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.75-7.65 (m, 2H),7.50-7.35 (m, 4H), 4.72 (ddd, J=10.3, 8.0, 5.1 Hz, 1H), 3.65 (s, 3H),3.28-3.05 (m, 2H), 1.29 (s, 9H). ¹³C NMR (101 MHz, DMSO) δ 173.00,167.21, 166.29, 154.39, 143.10, 130.85, 129.34, 129.27, 129.21, 129.03,127.21, 125.39, 125.10, 53.75, 52.04, 34.64, 30.92, 30.88.

(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2, 4-oxadiazol-5-yl)phenyl)propanoate

Prepared using General Procedure 5: To a solution of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid,INT-1 (10.0 mg, 0.026 mmol) in anhydrous DMF (1 mL) was added HOBt (5.27mg, 0.39 mmol) and EDC (7.48 mg, 0.39 mmol). After stirring for 2 h,(Z)-4-(heptyloxy)-N′-hydroxybenzimidamide (9.76 mg, 0.39 mmol) wasadded. The reaction mixture was stirred at room temperature for 2 h,partitioned between saturated aqueous NaHCO₃ (5 ml) and EA (5 mL), andconcentrated under reduced pressure to afford the intermediate(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(((4-(heptyloxy)benzimidamido)oxy)carbonyl) phenyl) propanoate. The intermediate was dissolved in DMF(1 mL) and heated to 100° C. for 18 h. The reaction mixture was cooledto room temperature and partitioned between EA (5 mL) and saturatedaqueous NaHCO₃ (5 mL). The organic layer was extracted with water (2×5mL) and brine (5 mL). The organic layer was dried over MgSO₄ andconcentrated. The brown oil was purified by preparative HPLC to afford4.5 mg (29%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl) propanoate. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₅: 597.3; nom/z observed, t_(R)=12.75 min (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.85(d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.74(d, J=8.5 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.12(d, J=8.9 Hz, 2H), 4.87-4.56 (m, 1H), 4.06 (t, J=6.5 Hz, 2H), 3.67 (s,3H), 3.32-3.13 (m, 4H), 1.74 (dd, J=14.2, 6.5 Hz, 2H), 1.51-1.37 (m,2H), 1.33 (s, 4H), 1.26 (d, J=20.2 Hz, 9H), 0.88 (t, J=6.9 Hz, 3H). ¹³CNMR (101 MHz, DMSO) δ 175.00, 171.91, 167.89, 166.27, 161.21, 154.37,143.68, 130.78, 130.30, 128.76, 127.80, 127.18, 125.07, 121.69, 118.21,115.07, 67.72, 53.61, 52.05, 36.15, 34.60, 31.20, 30.87, 28.54, 28.39,25.40, 22.02, 13.93.

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1, 2,4-oxadiazol-5-yl)phenyl)propanoic acid (Compound 1)

Prepared using General Procedure 4: To a solution of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoate (4.52 mg, 0.008 mmol) in MeOH (2 mL) was added of 1 N NaOH (1mL). The reaction mixture was stirred at 50° C. for 3 h. The resultingmixture was purified by preparative HPLC to afford 0.36 mg (8%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoic acid. LCMS-ESI (m/z) calculated for C₃₅H₄₁N₃O₅: 583.7; no m/zobserved, t_(R)=12.59 min (Method 2).

(S)-methyl 2-amino-3-(4-cyanophenyl)propanoate

To a solution of(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (1.0g, 3.44 mmol) in MeOH (20 mL) at 0° C. was slowly added thionyl chloride(818.1 mg, 6.89 mmol) over 1 h. The reaction was warmed to roomtemperature and stirred for 1 h. The solvent was removed under reducedpressure. The reaction mixture was washed with saturated aqueous NaHCO₃(20 ml) and extracted with DCM (3×10 ml). The organic layer was driedover MgSO₄ and concentrated. The crude product was purified bychromatography (EA/hexanes) to afford 789 mg (97%) of (S)-methyl2-amino-3-(4-cyanophenyl)propanoate as the HCl salt. LCMS-ESI (M/z)calculated for C₁₁H₁₂N₂O₂; 204.1; found 205.0 [M+H]⁺, t_(R)=3.25 min(Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 3H), 7.83 (d, J=8.3 Hz,2H), 7.51 (t, J=8.8 Hz, 2H), 4.37 (t, J=6.7 Hz, 1H), 3.68 (s, 3H), 3.23(qd, J=14.4, 7.7 Hz, 2H).

(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate

Prepared using General Procedure 3: To the solution of (S)-methyl2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM (15 mL)and DIEA (1.29 g, 9.96 mmol) was added 4-(tert-butyl)benzoyl chloride(981.3 mg, 4.99 mmol) at room temperature. The reaction was stirred for2 h and the reaction was partitioned between DCM and saturated aqueousNaHCO₃. The organic layer was dried over mgSO₄ and concentrated. Thecrude product was purified by chromatography (EA/hexanes) to afford 1.06g (88%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate. LCMS-ESI (m/zcalculated for C₂₂H₂₄N₂O₃: 364.2; found 365.3 [M+H]⁺, t_(R)=3.55 min(Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=8.0 Hz, 1H), 7.85-7.60(m, 4H), 7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m, 1H), 3.65 (s, 3H),3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H), 1.29 (s, 9H).

(S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl) propanoate (INT-2)

Prepared using General Procedure 2: To a stirring solution (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate (1.0 g, 2.74mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (572.2 mg,8.22 mmol) and TEA (1.38 g, 13.7 mmol). The reaction was heated to 85°C. for 2 h. The solvent was removed under reduced pressure and theresidue was diluted with water (20 mL) and extracted with DCM (3×10 mL).The combined organic layers were concentrated under reduced pressure.The crude material was crystallized from isopropanol (20 mL) to afford1.04 g (95%) of (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl)propanoate(INT-2) as a white solid. LCMS-ESI (m/z): calcd for: C₂₂H₂₇N₃O₄, 397.2;found 398.1 [M+1]⁺, t_(R)=2.26 min (Method 1). ¹H NMR (400 MHz, DMSO) δ10.19 (s, 1H), 9.57 (s, 1H), 8.78 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.4 Hz,2H), 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.3 Hz,2H), 4.79-4.49 (m, 1H), 3.65 (s, 3H), 3.15 (dt, J=13.6, 6.0 Hz, 2H),1.75 (d, J=13.6 Hz, 1H), 1.29 (s, 9H).

(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2, 4-oxadiazol-3-yl)phenyl)propanoate

Prepared using General Procedure 5: To a solution of4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL)were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol).After stirring for 2 h, (S, Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)-propanoate,INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirredat room temperature for 2 h, partitioned between saturated aqueousNaHCO₃ (15 mL) and EA (15 mL), and concentrated under reduced pressureto afford the intermediate (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimidoyl)phenyl)propanoate.The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for18 h. The reaction mixture was cooled to room temperature andpartitioned between EA (10 mL) and saturated aqueous NaHCO₃ (50 mL). Theorganic layer was extracted with water (2×10 mL) and brine (10 mL). Theorganic layer was dried over MgSO₄ and concentrated. The brown oil waspurified by chromatography (EA/hexanes) to afford 710 mg (77%) of(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₅: 597.3; nom/z observed, t_(R)=12.80 min (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.84(d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz,2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d,J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67(s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd,J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz,9H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 174.05, 170.87,133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06,125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32,33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1, 2,4-oxadiazol-3-yl)phenyl)propanoic acid (Compound 2)

Prepared using General Procedure 4: To a solution of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate(710.0 mg, 1.19 mmol) in MeOH (20 mL) was added 1 N NaOH (10 mL). Thereaction mixture was stirred at 50° C. for 3 h. The resulting mixturewas purified by chromatography (DCM/MeOH) to afford 218 mg (31%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoicacid as white solid. LCMS-ESI (m/z) calculated for C₃₅H₄₁N₃O₅; 583.3; nom/z observed, t_(R)=12.16 min (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.69(d, J=8.3 Hz, 1H), 8.16-8.02 (m, 2H), 7.98 (d, J=8.3 Hz, 2H), 7.74 (d,J=8.5 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.18 (d,J 9.0 Hz, 2H), 4.70 (ddd, J 10.8, 8.4, 4.5 Hz, 1H), 4.09 (t, J 6.5 Hz,2H), 3.30 (dd, J 13.8, 4.2 Hz, 1H), 3.17 (dd, J 13.8, 10.7 Hz, 1H), 1.74(dd, J 14.5, 6.7 Hz, 2H) 1.42 (dd, J 13.8, 6.1 Hz, 2H), 1.37-1.14 (m,14H), 0.87 (t, J 6.9 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 175.16, 173.00,167.96, 166.19, 162.55, 154.18, 142.11, 131.08, 129.95, 129.89, 127.14,126.92, 125.01, 124.39, 115.49, 115.37, 67.98, 53.72, 36.19, 34.58,31.19, 30.89, 28.46, 28.37, 25.36, 22.01, 13.92.

Compounds 3-11 and 13-61 were prepared from (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateINT-2 using General Procedures 5 and 4 sequentially.

Compounds 62-66 were prepared from (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateINT-2 using General Procedures 5, 6, and 4 sequentially.

(S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1, 2,4-oxadiazol-3-yl)phenyl)propanamido)acetic acid (Compound 67)

Prepared using General Procedures 7 and 8: To a solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoicacid, Compound 2(10.0 mg, 0.017 mmol) in anhydrous DMF (1 mL) was addedHOBt (3.52 mg, 0.027 mmol) and EDCI (4.88 mg, 0.027 mmol) at roomtemperature. After 2 h, tert-butyl 2-aminoacetate (3.49 mg, 0.027 mmol)was added and the reaction mixture stirred at room temperature for 2 h.LCMS analysis showed complete conversion to the intermediate. Thereaction mixture was partitioned between NaHCO₃ aqueous (5 ml) and DCM(1 mL), the organic layer was collected and concentrated by vacuum andthen was re-dissolved in 1 mL of DCM and 0.1 mL of TFA. The mixture washeated to 30° C. for 3 h. The final compound was purified by HPLC toafford 9.6 mg (88%) of(S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamido)aceticacid. LCMS-ESI (m/z) calculated for C₃₇H₄₄N₄O₆ 640.3; no m/z observed,t_(R)=11.51 min (Method 2). ¹H NMR (400 MHz, DMSO) δ: 8.60 (d, J=8.4 Hz,1H), 8.47 (t, J=5.7 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.2 Hz,2H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz,2H), 7.17 (d, J=8.8 Hz, 2H), 4.83 (d, J=8.1 Hz, 1H), 4.09 (t, J=6.4 Hz,2H), 3.94-3.69 (m, 2H), 3.34 (s, 2H), 3.26 (d, J=13.5 Hz, 1H), 3.15-3.01(m, 1H), 1.83-1.65 (m, 2H), 1.50-1.15 (m, 16H), 0.87 (t, J=6.7 Hz, 3H).¹³C NMR (101 MHz, DMSO) δ: 175.12, 171.58, 171.13, 167.99, 166.02,162.54, 154.10, 142.44, 131.16, 130.02, 129.89, 127.23, 126.81, 124.91,124.25, 115.50, 115.36, 67.97, 54.23, 40.10, 37.12, 34.57, 31.19, 30.88,28.46, 28.37, 25.36, 22.02, 13.93.

Compound 68 was prepared from Compound 5 using General Procedures 7, and8 sequentially.

Compound 69 was prepared from (S, Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateCompound 2 using General Procedure 7.

Compound 70 was prepared from (S, Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateCompound 2 using General Procedures 7 and 8 sequentially.

Compounds 71 and 72 were prepared from Methyl2-amino-2-(4-bromophenyl)acetate hydrochloride using General Procedures7, 1, 2, 5, and 4 sequentially.

Compounds 73 and 74 were prepared from (S)-methyl2-amino-4-(4-hydroxyphenyl)butanoate hydrobromide using GeneralProcedures 7, 9, 1, 2, 5, and 4 sequentially.

Compound 75 was prepared from (S)-methyl3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride using GeneralProcedures 7, 9, 1, 2, 5, and 4 sequentially.

4-(heptyloxy)benzohydrazide

To a stirred solution of 4-(heptyloxy)benzoic acid (679 mg, 2.87 mmol)in THF (5 mL) was added 1,1′-carbonyldiimidazole (559 mg, 3.45 mmol).After stirring at room temperature for 2 h, the solution was added to astirred mixture of hydrazine hydrate (0.729 mL, 5.75 mmol) in THF (2 mL)and stirred a further 2 h. The reaction mixture was poured onto water(20 mL) and stirred for 30 min. The resulting precipitate was collectedby filtration, washed with water (2×10 mL) then acetonitrile (3 mL) toafford 0.54 g (71%) of 4-(heptyloxy)benzohydrazide as a white solid.LCMS-ESI (m/z) calculated for C₁₄H₂₂N₂O₂: 250.3 found 251.0 [M+H]⁺,t_(R)=2.05 min. (Method 4).

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazine-carbonyl)phenyl)propanoate(INT-3)

To a stirring solution of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acidINT-1 (260 mg, 0.68 mmol) in THF (5 mL) were added 4-methylmorpholine(0.15 mL, 1.36 mmol) and isobutyl carbonochloridate (0.09 mL, 0.71mmol). After stirring at room temperature for 2 h,4-(heptyloxy)benzohydrazide (187 mg, 0.75 mmol) was added and stirringcontinued for another 2 h. The reaction mixture was poured onto NaHCO₃(50 mL) and extracted with DCM (3×20 mL). The combined organics weredried over MgSO₄ and evaporated. The crude product was purified bycolumn chromatography (100% EA in iso-hexanes) to afford 297 mg (71%) of(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoateINT-3 as an off-white foam. LCMS-ESI (m/z) calculated for C₃₆H₄₅N₃O₆:615.8 found 616.0 [M+H]⁺, t_(R)=2.89 min. (Method 4).

(S)-Methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3, 4-oxadiazol-2-yl)phenyl)propanoate

To a stirring solution (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoateINT-3 (127 mg, 0.21 mmol) and TEA (0.09 mL, 0.62 mmol) in DCM (4 mL) wasadded 2-chloro-1,3-dimethylimidazolidinium chloride (41.8 mg, 0.25mmol). The reaction mixture was stirred at room temperature for 18 hthen warmed to 40° C. for 1 h. The reaction mixture was cooled to roomtemperature, diluted with NaHCO₃ (15 mL), shaken, split through ahydrophobic frit and evaporated to afford 120 mg (95%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₅: 597.8; found598.0 [M+H]⁺, t_(R)=3.25 min. (Method 4).

Compound 76 was prepared using (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)propanoateand General Procedure 4.

2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4)

To a stirring solution of 1-(4-(heptyloxy)phenyl)ethanone (500 mg, 2.13mmol) in THF (8.5 mL) under nitrogen was added phenyltrimethylammoniumtribromide (842 mg, 2.24 mmol). The reaction mixture was stirred at roomtemperature for 2 h, filtered under vacuum and the captured solid washedwith THF. The combined liquors were concentrated to afford 919 mg (100%)of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 as a yellow oil.LCMS-ESI (m/z) calculated for C₁₅H₂₁BrO₂: 313.2; found 313.0 [M+H]⁺,t_(R)=2.12 min. (Method 4).

(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate

A solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone, INT-4 (166 mg,0.45 mmol) in acetonitrile (1 mL) was added to a solution of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acidINT-1 (190 mg, 0.50 mmol) and TEA (75.0 μl, 0.54 mmol) in acetonitrile(4 mL). The reaction mixture was stirred at room temperature for 18 hthen poured onto 0.5 M citric acid (30 mL) and extracted with EA (3×25mL). The combined organics were dried over MgSO₄, filtered andconcentrated. The residue was triturated with Et₂O (10 mL) and thefiltrate concentrated to afford 159 mg (49%) of(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate as a whitesolid. LCMS-ESI (m/z) calculated for C₃₇H₄₅NO₇: 615.8; found 616.0[M+H]⁺, t_(R)=2.76 min. (Method 4).

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate

To boron trifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added amixture of acetamide (763 mg, 12.9 mmol) and(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg,0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. Thereaction mixture was allowed to cool to room temperature, diluted withEA (15 mL) and extracted with NaHCO₃ (3×15 mL) and brine (15 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated. Theresidue was recrystallized from Et₂O (5 mL), filtered and rinsed withEt₂O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoateas an orange oil. LCMS-ESI (m/z) calculated for C₃₇H₄₄N₂O₅: 596.8; found597.0 [M+H]⁺, ^(t)R=3.11 min. (Method 4).

Compound 77 was prepared from (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoateusing General Procedure 4.

2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate

To stirring mixture of 4-(heptyloxy)benzoic acid (2.0 g, 8.46 mmol) inacetonitrile (30 mL) at room temperature was added TEA (1.24 mL, 8.87mmol) drop wise. The reaction mixture was stirred at room temperaturefor 1 h, poured onto 0.05 M citric acid (100 mL) and EA (10 mL) thenstirred for 10 min. The precipitate was isolated by filtration, washedwith water (30 mL) and iso-hexanes (2×10 mL) then dried in air to afford3.8 g (98%) of 2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate.LCMS-ESI (m/z) calculated for C₂₂H₂₅BrO₄: 433.3; found 455.0/457.0[M+Na]⁺, t_(R)=3.21 min. (Method 4).

4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole

To boron trifluoride etherate (0.322 mL, 2.5 mmol) was added2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate (1.0 g, 2.3 mmol) andacetamide (4.91 g, 83.0 mmol) in DCM (10 mL). The reaction mixture washeated to 50° C. then 140° C. for 16 h, DCM was distilled off. Thereaction mixture was cooled, diluted with acetonitrile and stirred atroom temperature for 1 h. The precipitate was isolated by filtration toafford 273 mg (23%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazoleas a brown solid. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrNO₂: 414.3;found 414.0 [M+H]⁺, t_(R)=3.00 min. (Method 4).

(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate

To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine(20.2 mg, 0.08 mmol). After the color disappeared, (R)-methyl2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (175 mg, 0.53 mmol) andfurther iodine (20.2 mg, 0.08 mmol) were added. After 30 min, themixture was de-gassed by bubbling through N₂ then treated with4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol),Pd₂dba₃ (12.2 mg, 0.01 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (10.9 mg,0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to50° C. for 2 h, cooled to room temperature and purified by columnchromatography (gradient of 15-95% EA in iso-hexanes) to afford 188 mg(65%) of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₁H₄₀N₂O₆: 536.6; found 537.0 [M+H]⁺,t_(R)=3.72 min. (Method 11).

Compound 78 was prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoateand 4-(tert-butyl)benzoic acid using General Procedures 8, 7 then 4.

2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl) thiazole

To a stirring solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4(1.37 g, 4.38 mmol) in EtOH (10 mL) were added 4-bromobenzothioamide(0.95 g, 4.38 mmol) and isopropanol (10 mL). The reaction mixture wasstirred at room temperature for 16 h. The solid was isolated byfiltration, washed with EtOH (5 mL) then taken up in DCM (10 mL) andNaHCO₃ (20 mL) and stirred for 1 h at room temperature. The solid wasisolated by filtration, washed with water (2×10 mL) and acetonitrile(2×4 mL) then dried to afford 1.02 g (52%) of2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole as a whitemicro-crystalline solid. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrNO_(S):429.1; found 430.0 [M+H]⁺, t_(R)=3.20 min. (Method 4).

(S)-Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)propanoate

To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) wasadded diiodine (44 mg, 0.17 mmol). When the color was discharged,(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. Afterstirring at room temperature for 30 min, the reaction mixture wasde-gassed by bubbling through N₂ then2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol),dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (23.8 mg,0.06 mmol), Pd₂dba₃(26 mg, 0.03 mmol) and DMF (2 mL) were added. Thereaction mixture was heated to 50° C. for 3 h, cooled and purified bycolumn chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%)of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)phenylpropanoate. LCMS-ESI (m/z) calculated forC₃₁H₄₀N₂O₅S: 552.3; no ion observed, t_(R)=3.37 min. (Method 4).

Compound 79 was prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy) phenyl)thiazol-2-yl) phenyl propanoate and 4-(tert-butyl)benzoic acid usingGeneral Procedures 8, 7 then 4.

4-(heptyloxy)benzothioamide

To stirring suspension of 4-(heptyloxy)benzamide (1.24 g, 5.29 mmol) inDME (20 mL) and THF (10 mL) was added2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (2.80g, 5.29 mmol). The reaction mixture was stirred at room temperature for16 h. The reaction mixture was concentrated onto silica and purified bycolumn chromatography (0-60% EA in iso-hexanes) to afford 1.4 g (62%) of4-(heptyloxy)benzothioamide as a yellow waxy solid. LCMS-ESI (m/z)calculated for C₁₄H₂₁NOS: 251.4; found 252.0 [M+H]⁺, t_(R)=3.13 min.(Method 6).

4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl) thiazole

To a stirring mixture of 4-(heptyloxy)benzothioamide (1.30 g, 5.17 mmol)in isopropanol (20 mL) was added 2-bromo-1-(4-bromophenyl)ethanone (1.44g, 5.17 mmol). The precipitate was collected by filtration and washedwith EtOH (2×5 mL). The filter cake was slurried with NaHCO₃ (2×20 mL),water (2×20 mL) then EtOH (2×5 mL) and dried to afford 926 mg (41%) of4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole as a pale yellowpowder. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrNOS: 429.1; found 430.0[M+H]⁺, t_(R)=3.41 min. (Method 4).

(S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate

To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) wasadded diiodine (35.4 mg, 0.14 mmol). When the color was discharged,further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol) wereadded. After 30 min, DMF (1 mL) was added and the mixture de-gassed bybubbling through N₂. To the reaction mixture were added4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol),Pd₂dba₃ (21 mg, 0.02 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (19 mg, 0.05mmol), the mixture was further de-gassed then heated to 50° C. for 3 h.The reaction mixture was cooled and purified by column chromatography(10-80% EA in iso-hexanes). The product obtained was taken into DCM (4mL) and washed with water (20 mL) and dried through a hydrophobic frit.The organics were suspended in ACN (4 mL) and concentrated to afford 432mg (83%) of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoateas a yellow foam. LCMS-ESI (m/z) calculated for C₃₁H₄₀N₂O₅S: 552.7; noion observed, t_(R)=3.36 min. (Method 4).

Compound 80 was prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoateand 4-(tert-butyl)benzoic acid using General Procedures 8, 7 then 4.4-(5-(4-(heptyloxy)phenyl) thiazol-2-yl)benzaldehyde

To a stirring suspension of 4-(thiazol-2-yl)benzaldehyde (349 mg, 1.84mmol), tricyclohexylphosphine (27 mg, 0.07 mmol), pivalic acid (64.2 μl,0.55 mmol), potassium carbonate (382 mg, 2.77 mmol) and palladium (II)acetate (8 mg, 0.04 mmol) in DMA (5.15 mL) under nitrogen was added asolution of 1-bromo-4-(heptyloxy)benzene (500 mg, 1.84 mmol) in DMA (1mL). The reaction mixture was evacuated and purged with nitrogen 3 timesthen heated at 100° C. for 6 h. Once cooled, the reaction mixture wasdiluted with EA (40 mL), washed with water (3×40 mL) and brine (40 mL).The organic phase was dried over MgSO₄, filtered and concentrated invacuo to afford a brown-green solid. The crude product was purified bychromatography (0-50% EA in hexanes) to afford 270 mg (37%) of4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde as an iridescentyellow solid. LCMS-ESI (m/z) calculated for C₂₃H₂₅NO₂S: 379.5; found380.0 [M+H]⁺, t_(R)=2.99 min. (Method 8).

Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate

A stirring mixture of 1,1,3,3-tetramethylguanidine (86 μl, 0.69 mmol)was added to a suspension of4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde (260 mg, 0.685 mmol)and methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate(185 mg, 0.62 mmol) in anhydrous THF (10 mL) under nitrogen, at −70° C.The reaction mixture was stirred at −70° C. for 1 h then at roomtemperature for 18 h. The reaction mixture was diluted with DCM (50 mL),washed with water (50 mL), passed through a phase separation cartridgeand the organic phase concentrated in vacuo to afford a yellow solid.The solid was triturated with EA/EtOH (20 mL) and the collected solidwashed with EtOH (10 mL) and Et₂O to afford 284 mg (79%) of methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate as a yellow solid. LCMS-ESI (m/z) calculated for C₃₁H₃₈N₂O₅S:550.7; found 551.0 [M+H]⁺, t_(R)=3.11 min. (Method 8).

Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptytyloxy)phenyl)thiazol-2-yl)phenyl)propanoate

A stirring mixture of Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate(50 mg, 0.091 mmol) dissolved in dioxane (5 mL) was hydrogenated usingan H-Cube hydrogenator (10% Pd/C, 30×4 mm, full hydrogen, 40° C., 1mL/min). The reaction mixture was concentrated in vacuo to afford 21 mg(29%) of methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)propanoateas a yellow solid. LCMS-ESI (m/z) calculated for C₃₁H₄₀N₂O₅S: 552.7;found 553.0 [M+H]⁺, t_(R)=1.85 min. (Method 8).

Compound 81 was prepared from Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy) phenyl)thiazol-2-yl) phenyl) propanoate and 4-(tert-butyl)benzoyl chlorideusing General Procedures 8, 3 then 4.

Compound 82 was prepared in a similar fashion to Compound 81 using4-(2-(4-(heptyloxy) phenyl) thiazol-5-yl)benzaldehyde in place of4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde.

(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3, 4-thiadiazol-2-yl)phenyl)propanoate

Prepared using INT-3: To a stirring solution of2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (65.7mg, 0.16 mmol) in THF (3 mL) was added (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoateINT-3 (100.0 mg, 0.16 mmol) and the mixture heated to 65° C. After 1 h,the reaction mixture was concentrated and purified by columnchromatography (10-100% EA in iso-hexanes) to afford 37.0 mg (29%) of(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoateas a yellow solid. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₄S: 613.8; noion observed, t_(R)=3.31 min. (Method 4).

Compound 83 was prepared from (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate using General Procedure4.

Compound 84 was prepared using 3-bromo-5-chloro-1,2,4-thiadiazole,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)propanoate (INT-5)

Prepared using General Procedure 9: A stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate hydrate (25g, 64.2 mmol) in DCM (100 mL) was treated with MgSO₄ (4.01 g, 33.7mmol). After 15 min, the mixture was filtered and washed with DCM (2×20mL). The organics were treated with N-ethyl-N-isopropylpropan-2-amine(17.41 g, 134.7 mmol) and stirred. This solution was treated with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight atroom temperature. The mixture was treated with water (50 mL) andsaturated aqueous NaHCO₃ (20 mL) and stirred vigorously for 10 min. Thelayers were separated and the organic layer was further washed withsaturated aqueous NaHCO₃ (2×50 mL), water (50 mL), and saturated aqueousNaHCO₃ (50 mL) and concentrated. The compound was purified bychromatography (EA/hexanes) to afford 26.85 g (79%) of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate INT-5. LCMS-ESI (m/z) calculated for C₂₂H₂₄F₃NO₇S: 503.1;found 526.1 [M+Na]⁺, t_(R)=4.12 min (Method 3).

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phenyl)propanoate(INT-6)

A solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-5 (26.85 g, 53.4 mmol), potassium acetate (15.71 g, 160.1 mmol),bis-pinacolatoborane (27.1 g, 106.7 mmol) and DMSO (100 mL) was degassedwith a steady flow of nitrogen gas for 5 minutes. To this solution wasadded PdCl₂(dppf) (1.95 g, 2.67 mmol) and the solution further degassedand kept under an atmosphere of nitrogen. The mixture was heated at 100°C. for 18 h then cooled to room temperature and diluted with EA (50 mL)and washed with saturated aqueous NaHCO₃ (20 mL), water (3×30 mL), driedover MgSO₄, filtered, and the solvent removed under reduced pressure.The compound was purified by column chromatography to give 11.10 g (41%)of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-6 as an oil. LCMS-ESI (m/z) calculated for C₂₇H₃₆BNO₆: 481.3; found504.3 [M+Na]⁺, t_(R)=4.21 min (Method 3). ¹H NMR (400 MHz, DMSO) δ 7.72(d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.42-7.11 (m, 6H), 4.98 (s,2H), 4.22-4.08 (m, 1H), 3.03 (dd, J=13.7, 5.2 Hz, 1H), 2.85 (dd, J=13.6,10.1 Hz, 1H), 1.36 (s, 6H), 1.30 (s, 9H), 1.22-1.13 (m, 6H).

(S)-Tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate (INT-7)

Prepared using General Procedure 10: A stirred mixture of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-6 (21.7 g, 45.0 mmol) and 5-bromo-2-iodopyrimidine (15.4g, 54.0 mmol) in dioxane (400 mL) with sodium carbonate decahydrate(25.7 g, 90 mmol) in water (100 mL) was de-gassed. PdCl₂(dppf) (0.99 g,1.4 mmol) was added and the mixture further de-gassed then heated toreflux for 5 h. The mixture was allowed to cool while stirringovernight. The mixture was poured onto water (1 L) and EA (300 mL) andstirred for 30 min. The mixture was filtered and the layers wereseparated. The aqueous layer was further extracted with EA (2×200 mL)and the combined organic layers were washed with water (2×100 mL) thenbrine (50 mL), dried over MgSO₄ and concentrated. Column chromatography(EA/hexanes) gave 14.84 g (63%) of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate INT-7. LCMS-ESI (m/z) calculated for C₂₅H₂₆BrN₃O₄: 511.1;found 534.0 [M+Na]⁺, t_(R)=2.97 min (Method 11).

(S)-Tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate (INT-8)

Prepared using General Procedure 10: A stirred solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7 (759 mg, 1.48 mmol), (4-(heptyloxy)phenyl)boronic acid (455 mg,1.93 mmol) and sodium bicarbonate (311 mg, 3.70 mmol) in acetonitrile (5ml), THF (5 ml), and water (4 ml) was degassed with N₂ for 5 min.Pd(dppf)Cl₂ (108 mg, 0.15 mmol) was added and the reaction was heated to110° C. in the microwave for 50 min. The reaction was diluted with EAand water then filtered. The organic phase was dried over MgSO4,filtered, and concentrated. The crude product was purified bychromatography on silica gel (EA/hexanes) to afford 591 mg (62%) of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-8 as a yellow solid. LCMS-ESI (m/z) calculated forC₃₈H₄₅N₃O₅: 623.8; no m/z observed, t_(R)=3.42 min (Method 8).

(S)-Tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoate(INT-9)

To a stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-8 (591 mg, 0.95 mmol) in EA (25 ml) was added Pd/C (101 mg, 0.09mmol) and the suspension degassed with H₂. The mixture was stirredvigorously under an atmosphere of H₂ overnight then filtered throughcelite and the filtrate was concentrated to give 405 mg (83%) of(S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9. LCMS-ESI (m/z) calculated for C₃₀H₃₉N₃O₃: 489.3; found: 490.2[M+H]⁺, t_(R)=2.35 min (Method 8).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid (Compound 85)

A stirred solution of (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 (1.34 g, 2.74 mmol) and 4-(tert-butyl)benzoic acid (0.54 g, 3.01mmol) in DMF (5 mL) and N-ethyl-N-isopropylpropan-2-amine (1.01 ml, 5.47mmol) was treated with HATU (1.09 g, 2.87 mmol). After stirring for 1 h,the mixture was treated with water (60 mL) and iso-hexanes (20 mL) andstirred for 1 h. The product was collected by filtration, washed withwater (3×10 mL) then iso-hexanes (10 mL) and dried in the vacuum oven.The ester was taken up in DCM (5 mL) and treated with TFA (5 mL). After2 h, the mixture was treated with toluene (5 mL) and evaporated. Theresidue was taken up in DMSO (6 mL) then treated with water (20 mL) andstirred for 1 h. The product was collected by filtration, washed withwater (3×15 mL) then acetonitrile (2×5 mL), and dried in the vacuum ovento give 1.40 g (85%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 as a white solid. LCMS-ESI (m/z) calculated forC₃₇H₄₃N₃O₄; 593.3; found: 594.0 [M+H]⁺, t_(R)=11.18 min (Method 9) and97% e.e. (Chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ 12.79 (br, s, 1H),9.16 (s, 2H), 8.66 (d, J=8.2 Hz, 1H), 8.45-8.27 (m, 2H), 7.89-7.69 (m,4H), 7.57-7.38 (m, 4H), 7.18-7.02 (m, 2H), 4.77-4.62 (m, 1H), 4.03 (t,J=6.5 Hz, 2H), 3.30-3.24 (m, 1H), 3.22-3.12 (m, 1H), 1.80-1.68 (m, 2H),1.48-1.20 (m, 17H), 0.96-0.82 (m, 3H).

Compounds 86-102, 104-158 and 296 were prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy) phenyl) pyrimidin-2-yl)phenyl)propanoateINT-8 using General Procedures 3 or 7 followed by 4 or 8.

(S)-Tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate (INT-10)

Prepared using General Procedure 10: A stirred solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7 (0.96 g, 1.86 mmol), (4-(tert-butyl)phenyl)boronic acid (0.43 g,2.42 mmol) and sodium bicarbonate (0.39 g, 4.66 mmol) in acetonitrile (5ml), THF (5 ml) and water (5 ml) was degassed with N₂ for 5 min.Pd(dppf)Cl₂ (0.136 g, 0.186 mmol) was added and the reaction was heatedto 110° C. in the microwave for 45 min. The reaction was diluted with EA(50 mL) and filtered over celite. The organic phase was washed withwater (100 mL) and concentrated. The crude product was purified bychromatography on silica gel (EA/isohexanes) to afford 757 mg (70%) of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl) propanoate INT-10 as a white powder. LCMS-ESI (m/z) calculatedfor C₃₅H₃₉N₃O₄: 565.3; no m/z observed, t_(R)=3.39 min (Method 8).

(S)-Tert-butyl2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-propanoate(INT-11)

To a stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-10 (757 mg, 1.34 mmol) in EA (100 ml) was added Pd/C (142 mg, 0.13mmol) and the suspension degassed with H₂. The mixture was stirredvigorously under an atmosphere of H₂ overnight then filtered throughcelite and the filtrate was concentrated to give 532 mg (88%) of(S)-tert-butyl2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-11. LCMS-ESI (m/z) calculated for C₂₇H₃₃N₃O₂: 431.3; found: 432.0[M+H]⁺, t_(R)=2.01 min (Method 4).

Compounds 159-181 were prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(tert-butyl) phenyl)pyrimidin-2-yl)phenyl)propanoateINT-11 using General Procedures 3 or 7 followed by 4 or 8.

Compound 182 was prepared in a manner analogous to 165 starting from(R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.

Compound 183 was prepared from(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)-2-(4-hydroxybenzamido)propanoicacid, Compound 114 using General Procedure 13.

Compounds 184-190 were prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy) phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 using General Procedures 13 and 8 sequentially.

Compound 191 was prepared in a manner analogous to 85 starting from(R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid (Compound 192)

A stirring solution of (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 (5.50 g, 11.23 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid(2.13 g, 11.57 mmol) in DMF (50 mL) and DIEA (6.22 ml, 33.70 mmol) wastreated portion wise with HATU (4.48 g, 11.79 mmol). After stirring for1 h, the mixture was treated with water (200 mL) and iso-hexanes (20 mL)and stirred for 10 min. The product was collected by filtration, washedwith iso-hexanes (2×30 mL), water (2×50 mL) then MeOH (20 mL) andiso-hexanes (30 mL). The ester was taken up in DCM (50 mL) and treatedwith TFA (10 mL). After 1 h, additional TFA (15 mL) was added. After afurther 5 h, the mixture was treated with toluene (20 mL) andconcentrated. The residue was washed with acetonitrile (25 mL) thentaken up in DMSO (20 mL) then treated with water (100 mL) and stirredfor 1 h. The product was collected by filtration, washed with water(4×50 mL) then acetonitrile (3×30 mL), and dried in a vacuum oven togive 5.30 g (75%)of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid, Compound 192 as an off-white solid. LCMS-ESI (m/z) calculated forC₃₅H₄₁N₃O₄S: 599.3; no m/z observed, t_(R)=11.10 min (Method 10). Thechiral purity was 98% e.e. (Chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ12.87 (s, 1H), 9.17 (s, 2H), 8.68 (d, J=8.3 Hz, 1H), 8.47-8.17 (m, 2H),7.96-7.71 (m, 2H), 7.64 (d, J=3.8 Hz, 1H), 7.55-7.29 (m, 2H), 7.26-7.02(m, 2H), 6.93 (d, J=3.8 Hz, 1H), 4.79-4.48 (m, 1H), 4.03 (t, J=6.5 Hz,2H), 3.27 (dd, J=13.9, 4.5 Hz, 1H), 3.12 (dd, J=13.9, 10.6 Hz, 1H),1.90-1.58 (m, 2H), 1.58-1.01 (m, 17H), 1.01-0.69 (m, 3H).

Compound 193 was prepared in a manner analogous to 192 starting from(R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate. Tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate

Prepared using General Procedure 7. Into a solution of4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were addedHATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and (S)-tert-butyl2-amino-3-(4-hydroxyphenyl) propanoate (10.0 g, 42.1 mmol). After 5 h,the reaction mixture was diluted with EA, washed with saturated aqueousNaHCO₃ and brine, then dried (Na₂SO₄), concentrated, and purified bychromatography (EA/hexanes) to provide 12.9 g (69%) of tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated forC₂₄H₃₁NO₄: 397.5; no m/z observed, t_(R)=3.59 min (Method 1). ¹H NMR(400 MHz, CDCl₃) δ7.71-7.65 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7Hz, 2H), 6.78-6.70 (m, 2H), 6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6Hz, 1H), 3.15 (qd, J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenylpropanoate (INT-12)

Prepared using General Procedure 9. Into a solution of tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate (8.0 g, 17.9 mmol) were added DIEA(3.7 mL, 1.2 mmol) and N-Phenyl bis(trifluoromethanesulfonimide) (7.0 g,19.7 mmol). After stirring for 36 h, the reaction mixture was dilutedwith DCM then washed with 10% aqueous citric acid and saturated aqueousNaHCO₃. The organic layer was dried over Na₂SO₄, and concentrated toprovide 9.5 g (100%) tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-12, which was used without further purification.LCMS-ESI (m/z) calculated for C₂₅H₃₀F₃NO₆S: 529.6; no m/z observed,t_(R)=4.42 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.65 (m, 2H),7.49-7.43 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.16 (m, 2H), 6.69 (d, J=7.0Hz, 1H), 4.94 (dt, J=6.9, 5.9 Hz, 1H), 3.24 (t, J=7.1 Hz, 2H), 1.41 (s,9H), 1.33 (s, 9H). Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-13)

Into a degassed solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-12 (9.5 g, 24 mmol), KOAc (7.0 g, 72 mmol), andbis-pinacolatoborane (9.1 g, 36 mmol) in DMSO (20 mL) was addedPd(dppf)Cl₂ (0.87 g, 1 mmol). The reaction mixture was heated at 100° C.for 12 h under an atmosphere of N₂. The reaction mixture was dilutedwith EA then washed with saturated aqueous NaHCO₃ and H₂O. The organiclayer was dried over Na₂SO₄, concentrated, and purified bychromatography (EA/hexanes) to provide 7.2 g (60%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13. LCMS-ESI (m/z) calculated for C₃₀H₄₂BNO₅: 507.5; no m/zobserved, t_(R)=4.53 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d,J=8.0 Hz, 2H), 7.72-7.67 (m, 2H), 7.48-7.43 (m, 2H), 7.21 (d, J=8.0 Hz,2H), 6.59 (d, J=7.4 Hz, 1H), 5.05-4.92 (m, 1H), 3.27 (qd, J=13.7, 5.4Hz, 2H), 1.47 (s, 9H), 1.36 (m, 21H). Tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate(INT-14)

Prepared using General Procedure 10. Into a degassed solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 (1.0 g, 2.0 mmol), Na₂HCO₃ (420 mg, 3.9 mmol), and5-bromo-2-iodopyrimidine (615 mg, 2.2 mmol) in 2/2/1 ACN/THF/H₂O wasadded Pd(dppf)Cl₂ (140 mg, 0.2 mmol). The reaction mixture was heated at110° C. for 1 h in a microwave reactor. The reaction mixture wasconcentrated, dissolved in DCM and washed with H₂O. The organic layerwas dried over Na₂SO₄, concentrated, and purified by chromatographyEA/hexanes) to provide 630 mg (58%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateINT-14. LCMS-ESI (m/z) calculated for C₂₈H₃₂BrN₄O₃: 538.5; no m/zobserved, t_(R)=4.66 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.84-8.78(s, 2H), 8.31 (t, J=7.0 Hz, 2H), 7.75-7.64 (m, 2H), 7.46-7.38 (m, 2H),7.30 (dd, J=12.9, 7.1 Hz, 2H), 6.65 (d, J=7.2 Hz, 1H), 5.10-4.94 (m,1H), 3.43-3.20 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H).

Compounds 194-236 were prepared from tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate INT-14 using GeneralProcedures 10 and 8 sequentially. Tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate

Prepared using General Procedure 7. Into a solution of5-(tert-butyl)thiophene-2-carboxylic acid (1.93 g, 10.0 mmol) in DMF (20mL) were added HATU (4.56 g, 12.0 mmol) and TEA (4.18 mL, 30.0 mmol).The mixture was stirred at room temperature for 30 min and(S)-tert-butyl 2-amino-3-(4-hydroxyphenyl) propanoate (2.37 g, 10.0mmol) was added. After 1 h, the reaction mixture was poured into 400 mLof ice-water and the solid was filtered. The solid was dissolved in DCMand EA, dried over MgSO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 3.6 g (89%) of tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate. LCMS-ESI (m/z)calculated for C₂₂H₂₉NO₄S: 403.2; found: 426.1 [M+Na]⁺, t_(R)=9.07 min(Method 2). Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy) phenyl) propanoate (INT-15)

Prepared using General Procedure 9. Into a solution of tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate (3.52 g, 8.72 mmol)were added DIEA (4.56 mL, 26.17 mmol) and N-phenylbis(trifluoromethanesulfonimide) (3.27 g, 9.16 mmol). After stirring for18 h, the reaction mixture was diluted with DCM then washed withsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by chromatography toprovide 4.10 g (87.6%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-15. LCMS-ESI (m/z) calculated for C₂₃H₂₈F₃NO₆S₂: 535.1; no m/zobserved, t_(R)=4.22 min (Method 3). Tert-butyl (S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-16)

Into a degassed solution of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-15 (3.89 g, 7.26 mmol), KOAc (2.14 g, 21.79 mmol), andbis-pinacolatoborane (2.40 g, 9.44 mmol) in DMSO (50 mL) was addedPd(dppf)Cl₂ (0.27 g, 0.36 mmol). The reaction mixture was heated at 100°C. for 18 h under an atmosphere of N₂. The reaction mixture was pouredinto 600 mL of ice-water and the solid was filtered. The precipitate wasdiluted with EA, dried over MgSO₄, concentrated, and purified bychromatography (EA/hexanes) to provide 3.68 g (99%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-16. LCMS-ESI (m/z) calculated for C₂₈H₄₀BNO₅S: 513.3; no m/zobserved, t_(R)=4.51 min (Method 3). Tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate(INT-17)

Prepared using General Procedure 10. Into a degassed solution oftert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-16 (510 mg, 1.0 mmol) and 5-bromo-2-iodopyrimidine (570 mg, 2.0mmol) in 2/2/1 ACN/THF/saturated aqueous NaHCO₃ (10 mL) was addedPd(dppf)Cl₂ (30 mg, 0.4 mmol). The reaction mixture was heated at 120°C. for 1 h in a microwave reactor. The reaction mixture was diluted withwater (100 mL) and EA (50 mL) and filtered over Celite. The aqueouslayer was extracted with EA (3×30 mL) and the combined organic layer wasdried over MgSO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 342 mg (63%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17. LCMS-ESI (m/z) calculated for C₂₆H₃₀BrN₃O₃: 543.1; found: 488.0[M-tBu+H]⁺, t_(R)=10.95 min (Method 2).

Compounds 237-247 were prepared from tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 using General Procedures 10 and 8 sequentially. Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)-propanoate(INT-18)

Prepared using General Procedure 1. Into a degassed solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateINT-14 (100 mg, 0.190 mmol), and Zn(CN)₂ (44 mg, 0.370 mmol) in NMP (5mL) was added Pd(Ph₃)₄(2 mg, 0.002 mmol). The mixture was heated for 45min at 80° C. in a microwave reactor then partitioned between DCM andH₂O. The organic layer was dried over Na₂SO₄, concentrated, and purifiedby chromatography (EA/hexanes) to provide 75 mg (84%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoateINT-18. LCMS-ESI (m/z) calculated for C₂₉H₃₂N₄O₃: 484.60; no m/zobserved, t_(R)=4.17 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s,2H), 8.38 (d, J=7.9 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.46-7.35 (m, 2H),7.33 (d, J=7.9 Hz, 2H), 6.77 (d, J=6.8 Hz, 1H), 4.96 (d, J=6.1 Hz, 1H),3.27 (dd, J=13.1, 8.0 Hz, 2H), 1.37 (d, J=34.5 Hz, 9H), 1.26 (d, J=21.0Hz, 9H). Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(N-hydroxycarbamimidoyl)-pyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 2. A solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoateINT-18 (35 mg, 0.07 mmol), hydroxylamine (25 μL, 0.36 mmol, 50% solutionin H₂O), and NEt₃ (11 μL, 0.08 mmol) in EtOH (5 mL) was heated at 80° C.for 1.5 h. The reaction mixture was concentrated, dissolved in DCM andwashed with H₂O to provide 22 mg of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(N-hydroxycarbamimidoyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated forC₂₉H₃₅N₅O₄: 517.6; found 462.2 [M−^(t)Bu+H]⁺, t_(R)=3.72 min (Method 1).¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.67(dd, J=8.5, 2.1 Hz, 2H), 7.40 (dd, J=9.2, 8.0 Hz, 2H), 7.34 (dd, J=10.3,8.4 Hz, 2H), 6.74 (dd, J=7.1, 4.7 Hz, 1H), 5.00 (q, J=5.6 Hz, 1H), 2.83(d, J=5.3 Hz, 2H), 1.44 (s, 9H), 1.28 (d, J=22.0 Hz, 9H). Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1, 2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoate (Compound 248)

Prepared using General Procedure 5. A solution of heptanoic acid (7 mg,0.05 mmol), HOBt (12 mg, 0.09 mmol) and EDC (13 mg, 0.09 mmol) washeated at 80° C. for 2 h. The reaction mixture was diluted with EtOAcand washed with NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The resulting mixture was dissolved in EtOH (2 mL) andheated for 45 min at 80° C. in a microwave reactor. The mixture wasconcentrated and purified by preparatory HPLC to provide 1.5 mg oftert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₆H₄₅N₅O₄: 611.8; no m/z observed,t_(R)=5.5 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 2H), 8.44(d, J=8.3 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.38(d, J=8.3 Hz, 2H), 6.80 (d, J=7.3 Hz, 1H), 5.04 (dd, J=12.7, 5.5 Hz,1H), 3.37 (ddd, J=18.9, 13.8, 5.5 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.92(dt, J=15.3, 7.5 Hz, 2H), 1.49 (s, 9H), 1.44-1.28 (m, 15H), 0.93 (t,J=7.1 Hz, 3H).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl) phenyl)propanoate was deprotected using GeneralProcedure 8 to provide 1.4 mg (6% overall) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoic acid Compound 248. LCMS-ESI (m/z) calculated for C₃₂H₃₇N₅O₄:555.68; no m/z observed, t_(R)=11.03 min (Method 2). ¹H NMR (400 MHz,CDCl₃) δ 9.41 (s, 2H), 8.47 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H),7.42 (dd, J=15.1, 8.4 Hz, 4H), 6.60 (d, J=6.8 Hz, 1H), 5.21-4.95 (m,1H), 3.43 (ddd, J=20.0, 14.0, 5.6 Hz, 2H), 3.05-2.90 (m, 2H), 1.98-1.76(m, 2H), 1.55-1.22 (m, 15H), 0.91 (t, J=7.0 Hz, 3H). Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 10. To a degassed solution oftert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido) propanoate INT-17 (180mg, 0.3 mmol), sodium carbonate (70 mg, 0.7 mmol) and4-hydroxyphenylboronic acid (55 mg, 0.4 mmol) in 5 mL of 2/2/1ACN/THF/H₂O was added Pd(dppf)Cl₂ (24 mg, 0.03 mmol). The reactionmixture was heated at 110° C. for 45 min in a microwave reactor. Themixture was filtered through celite, concentrated, then dissolved in DCMand washed with H₂O. The organic layer was concentrated and purified byprep HPLC to provide 131 mg (78%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl) propanoate. LCMS-ESI (m/z) calculated forC₃₂H₃₅N₃O₄S: 557.7; no m/z observed, t_(R)=4.08 min (Method 1). ¹H NMR(400 MHz, CDCl₃) δ 8.98 (s, 2H), 8.35 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.6Hz, 2H), 7.40-7.31 (m, 3H), 6.94 (d, J=8.5 Hz, 2H), 6.81 (d, J=3.8 Hz,1H), 6.51 (d, J=7.5 Hz, 1H), 5.00 (dd, J=12.9, 5.8 Hz, 1H), 3.28 (qd,J=13.8, 5.6 Hz, 2H), 1.47 (s, 9H), 1.39 (s, 9.H).

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(decyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid (Compound 249)

Prepared using General Procedures 12. To a solution of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoate (20 mg, 0.04 mmol) in DMF (0.5 mL) wereadded 1-bromodecane (8 μL, 0.05 mmol) and K₂CO₃ (8 mg, 0.05 mmol). Thereaction mixture was heated at 40° C. for 18 h, then diluted with DCMand washed with H₂O. The organic layer was dried over Na₂SO₄ andconcentrated. The crude material was deprotected using General Procedure8 then purified by preparatory HPLC to provide 3.9 mg (17%) of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(decyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid compound 249. LCMS-ESI (m/z) calculated for C₃₈H₄₇N₃O₄S: 641.9; nom/z observed, t_(R)=13.49 min (Method 2). ¹H NMR (400 MHz, CDCl₃) δ 9.01(s, 2H), 8.36 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.44 (d, J=8.2Hz, 2H), 7.33 (d, J=3.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.80 (d, J=3.8Hz, 1H), 6.54 (d, J=6.8 Hz, 1H), 5.13 (d, J=6.8 Hz, 1H), 4.01 (t, J=6.6Hz, 2H), 3.44 (d, J=4.9 Hz, 2H), 1.91-1.72 (m, 2H), 1.47 (dd, J=15.0,7.3 Hz, 2H), 1.38 (s, 9H), 1.28 (s, 12H), 0.88 (t, J=6.8 Hz, 3H).

Compounds 250-252 were prepared from tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl) propanoate using General Procedure 12 followed byGeneral Procedure 8.

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoicacid (Compound 253)

Prepared using General Procedure 11. Into a degassed solution of INT-14(50 mg, 0.09 mmol), sodium tert-butoxide (18 mg, 0.19 mmol) and4-tert-butylpiperidine HCl (23 mg, 0.11 mmol) in dioxane (2.5 mL) wereadded Pd₂(dba)₃ (9 mg, 0.01 mmol) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (6 mg, 0.015mmol). The reaction mixture was heated for 45 min at 120° C. in amicrowave reactor. The mixture was diluted with EA and washed withNaHCO₃. The organic layer was dried over Na₂SO₄, concentrated, andpurified by preparatory HPLC. The isolated intermediate was deprotectedusing General Procedure 8 to provide 2.9 mg (6%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoicacid Compound 253. LCMS-ESI (m/z) calculated for C₃₃H₄₂N₄O₃: 542.7;found 543.3 [M+H]⁺, t_(R)=10.79 min (Purity). ¹H NMR (400 MHz, CDCl₃) δ8.52 (s, 2H), 8.23 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.44 (dd,J=11.3, 8.4 Hz, 4H), 6.79 (d, J=6.8 Hz, 1H), 5.18 (d, J=6.5 Hz, 1H),3.89 (d, J=11.9 Hz, 2H), 3.47 (d, J=5.2 Hz, 2H), 2.83 (t, J=11.5 Hz,2H), 1.88 (d, J=12.0 Hz, 2H), 1.52-1.37 (m, 2H), 1.34 (s, 9H), 1.24 (dd,J=24.7, 12.8 Hz, 1H), 0.92 (s, 9H).

Compound 254 was prepared from INT-14 using General Procedure 11 thenGeneral Procedure 8.

Tert-butyl(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)-benzamido)propanoate

Into a solution of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoateINT-18 (34 mg, 0.07 mmol) in DMF (2 mL) were added NH₄Cl (7.5 mg, 1.4mmol) and NaN₃ (7 mg, 0.1 mmol). The reaction mixture was heated at 100°C. for 3 h then diluted with EA and washed with NaHCO₃. The organiclayer was dried over Na₂SO₄, concentrated, and purified by preparatoryHPLC to provide 4.6 mg (12%) of tert-butyl(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate.LCMS-ESI (m/z) calculated for C₂₉H₃₃N₇O₃: 527.6; no m/z observed,t_(R)=3.83 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 2H), 8.42(d, J=8.1 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.43(d, J=8.2 Hz, 2H), 7.11 (d, J=7.8 Hz, 1H), 5.13 (dd, J=14.4, 7.1 Hz,1H), 3.28 (ddd, J=21.0, 13.6, 6.7 Hz, 2H), 1.47 (d, J=6.8 Hz, 9H), 1.33(s, 9H).

Compound 255 was prepared from tert-butyl(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateusing General Procedure 12 then General Procedure 8.

Compound 256 was prepared from INT-14 and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one usingGeneral Procedures 10, 12 and 8.

Compound 257 was prepared from INT-14 and 6-Hydroxypyridine-3-boronicacid pinacol ester using General Procedures 10, 12 and 8.

Compound 258 was prepared from INT-13 and5-(benzyloxy)-2-chloropyrimidine using General Procedure 10, followed byGeneral Procedure 8.

Compounds 259 and 260 were prepared from INT-14 and the appropriateboronic acid using General Procedures 10 then 8.

Tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate

To a stirring solution of 1-bromo-4-(heptyloxy)benzene (447 mg, 1.65mmol) in dioxane (5 mL) were added tert-butyl3-oxopiperazine-1-carboxylate (330 mg, 1.65 mmol), copper I iodide (31.4mg, 0.17 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (234 mg,1.65 mmol) and potassium carbonate (456 mg, 3.30 mmol). The reactionmixture was heated at 120° C. for 16 h. The reaction mixture was passedthrough a plug of celite, eluted with EA (50 mL). The organics werewashed with ammonium chloride (25 mL), water (25 mL) and brine (25 mL)then dried over MgSO₄ and concentrated to afford 602 mg (89%) oftert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate.LCMS-ESI (m/z) calculated for C₂₂H₃₄N₂O₄: 390.5; found 319.0 [M+H]⁺,t_(R)=2.90 min. (Method 4).

1-(4-(heptyloxy)phenyl)piperazin-2-one

To tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate (540mg, 1.38 mmol) was added 4M HCl in dioxane (2.07 mL, 8.30 mmol). Thereaction mixture was stirred at room temperature for 2 h. Theprecipitate was filtered, washed with hexane (5 mL) and dried. The crudeproduct was purified by column chromatography (79/20/1 DCM/MeOH/NH₄) toafford 325 mg (80%) of 1-(4-(heptyloxy)phenyl)piperazin-2-one as acolorless solid. LCMS-ESI (m/z) calculated for C₁₇H₂₆N₂O₂: 290.4; found291.0 [M+H]⁺, t_(R)=1.49 min. (Method 4).

Compound 261 was prepared from INT-12 and1-(4-(heptyloxy)phenyl)piperazin-2-one using General Procedures 11 and8.

Compound 262 was prepared in a similar fashion from INT-12 and1-(4-(heptyloxy)phenyl)imidazolidin-2-one using General Procedures 11and 8.

Compound 263 was prepared using (S)-methyl2-amino-3-(4-nitrophenyl)propanoate hydrochloride, 4-(tert-butyl)benzoicacid and 1-(4-(heptyloxy)phenyl)piperidin-4-one using General Procedures7, 14, 15 then 4.

Tert-butyl 4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate

To a stirring solution of 1-bromo-4-(heptyloxy)benzene (668 mg, 2.46mmol) in THF (5 mL) at −78° C. was added butyllithium (985 μl, 2.46mmol). After 30 min, a solution of tert-butyl4-oxopiperidine-1-carboxylate (491 mg, 2.46 mmol) in THF (2 mL) wasadded. After 10 min, the cooling bath was removed and the reactionmixture stirred for 16 h. The reaction mixture was poured onto NH₄Cl (50mL) and extracted with Et₂O (3×20 mL). The combined organics were washedwith water (20 mL), dried over MgSO₄ and evaporated. The crude productwas purified by column chromatography (5-70% AcMe in iso-hexanes) toafford 0.4 g (33%) of tert-butyl4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate. LCMS-ESI(m/z) calculated for C₂₃H₃₇NO₄: 391.5; found 414.0 [M+Na]⁺, t_(R)=2.24min. (Method 4).

4-(4-(heptyloxy)phenyl)piperidine (INT-19)

To a stirring solution of tert-butyl4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate (388 mg, 0.99mmol) and triethylsilane (791 μl, 4.95 mmol) in DCM (2 mL) cooled to−30° C. was slowly added 2,2,2-trifluoroacetic acid (379 μl, 4.95 mmol)in a drop-wise fashion. The reaction mixture was allowed to warm slowlyand stirring continued for 16 h. The reaction mixture was poured ontoice-water/NaOH (50 mL/5 mL, 2 M) and extracted with DCM (3×20 mL). Thecombined organic extracts were washed successively with water (50 mL)and NaHCO₃ (20 mL), dried over MgSO₄ and evaporated to afford 166 mg(58%) of 4-(4-(heptyloxy)phenyl)piperidine INT-19 as a white, waxysolid. LCMS-ESI (m/z) calculated for C₁₈H₂₉NO: 275.4; found 276.0[M+H]⁺, t_(R)=2.88 min. (Method 11).

Compound 264 was prepared using INT-12 and INT-19 using GeneralProcedures 11 then 8.

Compound 265 was prepared in a similar fashion to 264 using INT-12 and3-(4-(heptyloxy)phenyl)pyrrolidine using General Procedures 11 then 8.

Compound 266 was prepared using INT-12 and1-([1,1′-biphenyl]-4-yl)piperazine using General Procedures 11 then 8.

Compound 267 was prepared using INT-12, tert-butyl4-(4-hydroxyphenyl)piperazine-1-carboxylate and 1-bromoheptane usingGeneral Procedures 12, 8, 11 then 8.

Compound 268 was prepared using INT-12, tert-butyl1,4-diazepane-1-carboxylate and 1-bromo-4-(heptyloxy)benzene usingGeneral Procedures 11, 8, 11 then 8.

Compound 269 was prepared using 5-bromo-2-iodopyridine, INT-13 and(4-(heptyloxy)phenyl)boronic acid using General Procedures 10, 10, and 8sequentially.

Compound 270 was prepared using 5-bromo-2-iodopyridine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

Compound 271 was prepared using 5-bromo-2-iodopyrimidine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

Compound 272 was prepared using 2-bromo-5-iodopyrazine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

Compound 273 was prepared using 3-chloro-6-iodopyridazine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1, 2, 4-triazine (INT-20)

To a stirring solution of 4-bromobenzohydrazide (1.85 g, 8.62 mmol) inethanol (10 mL) was added acetic acid (1 mL). The reaction mixture wasstirred at 60° C. for 30 min then2-bromo-1-(4-(heptyloxy)phenyl)ethanone (1.35 g, 4.31 mmol) INT-4 andsodium acetate (0.389 g, 4.74 mmol) were added and the mixture heated toreflux for 30 min. The reaction mixture was cooled to room temperatureand the resultant precipitate was filtered and washed with iso-hexanes(20 mL) then dried. The solid was dissolved in NMP and heated to 120° C.for 16 h. The crude material was cooled to room temperature, dilutedwith Et₂O (4 mL), filtered, triturated with ethanol (3×2 mL), filteredand dried to afford 241 mg (13%) of3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine INT-20 as anorange solid. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrN₃O: 425.1; found426.3 [M+H]⁺, t_(R)=3.40 min (Method 8).

Compound 274 was prepared in a similar fashion to 79 using3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine INT-20 in placeof 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole.

6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1, 2, 4-triazine (INT-21)

To a stirring solution of 4-(heptyloxy)benzohydrazide (400 mg, 1.60mmol) in ethanol (15 mL) was added acetic acid (1 mL). The reactionmixture was stirred at 60° C. for 30 min then2-bromo-1-(4-bromophenyl)ethanone (222 mg, 0.80 mmol) and sodium acetate(72.1 mg, 0.88 mmol) were added and the solution heated to reflux for 2h. The reaction mixture was cooled to room temperature and the resultantcrystals were filtered, washed with iso-hexanes (20 mL) then dried toafford 108 mg (31%) of6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazine INT-21.LCMS-ESI (m/z) calculated for C₂₂H₂₄BrN₃O: 425.1; found 426.1 [M+H]⁺,t_(R)=3.38 min (Method 8).

Compound 275 was prepared in a similar fashion to 274 using6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazine INT-21 in placeof 3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine.

Compound 276 was prepared using 274 using General Procedures 7 and 8.

Compounds 277 and 278 were prepared using INT-16 and5-bromo-2-iodopyridine using General Procedures 10, 10, and 8sequentially.

Compounds 279 and 280 were prepared using INT-16 and3-chloro-6-iodopyridazine using General Procedures 10, 10, and 8sequentially.

Compounds 281 and 282 were prepared using INT-16 and2-bromo-5-iodopyrazine using General Procedures 10, 10, and 8sequentially.

Compound 283 was prepared from Compound 279 and tert-butyl glycinateusing General Procedures 7 and 8 sequentially.

Compound 284 was prepared from Compound 281 and tert-butyl glycinateusing General Procedures 7 and 8 sequentially.

Compound 285 was prepared from Compound 277 and tert-butyl glycinateusing General Procedures 7 and 8 sequentially.

2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate

To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.3 g,4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN (30 mL) wasadded TEA (0.72 ml, 5.2 mmol). After stirring overnight, the mixture waspoured onto aq. citric acid and EA then stirred for 10 min before thesolid was collected by filtration. The cake was washed with water andiso-hexanes then dried to provide 905 mg (57%) of2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate. LCMS-ESI (m/z)calculated for C₂₂H₂₅BrO₄: 432.1; found 433.2 [M+H]⁺, t_(R)=3.24 min(Method 8).

2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole

To a solution of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate (905mg, 2.09 mmol) intoluene (6 ml) was added CH₃COONH₄ (1600 mg, 20.9mmol). After heating overnight at 115° C., the reaction mixture wasdiluted with aq. NaHCO₃ and extracted into DCM. The organic layers werecombined, dried over MgSO₄, filtered, and the solvent was removed underreduced pressure. The crude reaction mixture was purified bychromatography (EA/hexanes) to provide 370 mg (33%) of2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole. LCMS-ESI (m/z)calculated for C₂₂H₂₅BrN₂O: 412.1; found 413.2 [M+H]⁺, t_(R)=2.33 min(Method 8).

2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a solution of 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole(370 g, 900 mmol) in DMF (4 ml) was added NaH (40 mg, 980 mmol). After 2h, 2-(trimethylsilyl)ethoxymethyl chloride (160 g, 990 mmol) in THF (2ml) was added dropwise and reaction mixture was stirred overnight. Thereaction mixture was diluted with EA and washed with aq. NaHCO₃. Theorganics were dried over MgSO₄, filtered, and the solvent was removedunder reduced pressure. The crude product was purified by chromatography(EA/hexane) to afford 32 mg (65%) of2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazoleas a tan solid. LCMS-ESI (m/z) calculated for C₂₈H₃₉BrN₂O₂Si: 542.2;found 543.3 [M+H]⁺, t_(R)=3.35 min (Method 8).

(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate

A stirred suspension of zinc (68 mg, 1.03 mmol) in DMF (2 mL) wastreated with I₂ (12 mg, 0.05 mmol). After the color disappeared,((R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (110 mg,0.34 mmol) and further I₂ (12 mg, 0.05 mmol) were added. After 30 min,the mixture was de-gassed then2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(170 mg, 0.31 mmol),dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (7 mg, 0.02mmol) and Pd₂(dba)₃ (8 mg, 7.8 mol) were added. After furtherde-gassing, DMF (2 mL) was added and the reaction mixture was heated at50° C. overnight. The reaction mixture purified by column chromatography(EA/hexane) to provide 55 mg (25%) of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoateas a colorless oil. LCMS-ESI (m/z) calculated for C₃₇H₅₅N₃O₆Si: 665.9;found 666.4 [M+H]⁺, t_(R)=3.10 min (Method 8).

(S)-methyl2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)-propanoate

(S)-methyl2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoatewas prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl) propanoate using General Procedure 8. LCMS-ESI (m/z) calculatedfor C₂₆H₃₃N₃O₃: 435.6; found 436.3 [M+H]⁺, t_(R)=1.43 min (Method 8).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoicacid hydrochloride (Compound 286)

To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol),(S)-methyl2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate(55 mg, 0.13 mmol), and TEA (53 μl, 0.38 mmol) in DMF (1 mL) was addedHATU (53 mg, 0.14 mmol). The reaction mixture was stirred at roomtemperature for 2 h, diluted in DCM, and washed aq. NaHCO₃. The organiclayer was dried, concentrated and purified by chromatography (EA/hexane)to provide 14 mg (17%) of methyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₇H₄₅N₃O₄: 595.8; found 596.4 [M+H]⁺,t_(R)=2.33 min. (Method 8).

The isolated ester intermediate was deprotected using General Procedure4 to provide 14 mg (17.5%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoicacid hydrochloride Compound 286 as a light tan solid. LCMS-ESI (m/z)calculated for C₃₆H₄₃N₃O₄: 581.8; found 582.4 [M+H]⁺, t_(R)=6.56min(Method 9).

4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole

Into a vial was charged (4-(heptyloxy)phenyl)boronic acid (1.00 g, 4.24mmol), 4-bromo-1H-imidazole (0.31 g, 2.1 mmol), Cu-(TMEDA)₂(OH)₂Cl₂(0.10 g, 0.21 mmol) and DCM (12 ml). After stirring at room temperaturefor 42 h, the mixture was purified by chromatography (EA/hexane) toprovide 80 mg of impure product. Further purification by chromatography(CAN/DCM) provided 42 mg (6%) of4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole as a colourless oil.LCMS-ESI (m/z) calculated for C₁₆H₂₁BrN₂O: 336.1; found 337.1 [M+H]⁺,t_(R)=2.71 min (Method 8).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-4-yl)phenyl)propanoicacid (Compound 287)

Prepared using General Procedure 10. Into a vial containing INT-13 (96mg, 0.19 mmol) and 4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole (64 mg,0.19 mmol) in 2/2/1 THF/CAN/H₂O (3 mL) was added Na₂CO₃ (40 mg, 0.38mmol). The reaction mixture was degassed and Pd(dppf)Cl₂ (14 mg, 0.02mmol) was added. After heating at 120° C. for 30 min in a microwavereactor, the mixture was diluted with EA, washed with aq. NaHCO₃, driedover MgSO₄ and concentrated. Purification by chromatography (EA/hexanes)provided 14 mg (12%) of the intermediate tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-4-yl)phenyl)propanoateas a white solid.

The intermediate was deprotected according to General Procedure 8 toprovide 9 mg (8%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-4-yl)phenyl)propanoicacid, Compound 287 as a white solid. LCMS-ESI (m/z) calculated forC₃₆H₄₃N₃O₄: 581.3; found 582.2 [M+H]⁺, t_(R)=8.33 min (Method 9).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoicacid (Compound 288)

Prepared using General Procedure 10. Into a vial containing INT-13 (100mg, 0.20 mmol) and4-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole (63 mg, 0.201mmol) in 2/1 ACN/H₂O (3 mL) was added sat aq. NaHCO₃ (670 μL, 0.60mmol). The reaction mixture was degassed and Pd(dppf)Cl₂ (15 mg, 0.02mmol) was added. After heating at 120° C. for 60 min in a microwavereactor, the mixture was diluted with DCM, washed with aq. NaHCO₃,passed through a phase separation cartridge, and concentrated.Purification by chromatography (EA/hexane) provided 58 mg (47%) of theintermediate tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₄₀H₄₃N₃O₃: 613.8; found614.0 [M+H]⁺, t_(R)=3.02 min (Method 8). The intermediate was stirred in4M HCl/dioxane for 132 h and filtered. The resulting solid was washedwith hexane to provide 13 mg of solid product. The filtrate was loadedonto a strong anion exchange (SAX) column, washed with MeOH, and elutedwith 5% AcOH in MeOH. The elution liquors were combined with thetrituration solid and concentrated in vacuo to afford 18 mg (32%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoicacid 288 as a white solid. LCMS-ESI (m/z) calculated for C₃₆H₃₅N₃O₃:557.3; found 558.0 [M+H]⁺, t_(R)=9.37 min (Method 9).

Methyl2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate

Prepared using General Procedure 7. To a solution of methyl2-amino-2-(4-bromophenyl)acetate, HCl (730 mg, 2.6 mmol),5-(tert-butyl)thiophene-2-carboxylic acid (480 mg, 2.6 mmol) and TEA(1090 μl, 7.8 mmol) in DMF (10 mL) was added HATU (1090 mg, 2.9 mmol).After stirring overnight, the reaction mixture was diluted with EA (100mL) and washed with 1M HCl (100 mL) and brine. The organic layer wasdried over Mg₂SO₄, concentrated, and purified by chromatography(EA/hexane) to provide 900 mg (76%) of methyl2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate as awhite powder. LCMS-ESI (m/z) calculated for C₁₈H₂₀BrNO₃S: 410.3; found412.0 [M+2]⁺, t_(R)=2.71 min (Method 8).

Methyl 2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

Prepared using General Procedure 10. A solution of2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate (900mg, 2.2 mmol), KOAc (650 mg, 6.6 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (670 mg, 2.6mmol) in DMSO (10 mL) at 40° C. was de-gassed. PdCl₂dppf (80 mg, 0.11mmol) was added and the mixture was heated at 100° C. for 3 h. Thereaction mixture was purified by chromatography (EA/hexane with 1% TEA)to provide 491 mg (41%) of methyl2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate.LCMS-ESI (m/z) calculated for C₂₄H₃₂BNO₅S: 457.4; found 458.0 [M+H]⁺,t_(R)=2.89 min (Method 8).

2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)aceticacid

Prepared using General Procedure 10. A mixture of methyl2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(320 mg, 0.71 mmol) and 5-bromo-2-iodopyrimidine (220 mg, 0.78 mmol) inTHF (2 mL) and ACN (2 mL) was treated with saturated aq. NaHCO₃ (1600μl, 1.40 mmol) and de-gassed (N₂ bubbling). PdCl₂dppf (26 mg, 0.04 mmol)was added and the mixture was heated at 120° C. for 30 min in amicrowave reactor. The mixture was poured onto H₂O (30 mL), acidifiedwith AcOH and extracted with EA (3×15 mL). The combined organics weredried over MgSO₄, evaporated, and purified by chromatography (EA/hexanewith 1% AcOH) to provide 160 mg (46%) of2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)aceticacid as a white solid. LCMS-ESI (m/z) calculated for C₂₁H₂₀BrN₃O₃S:473.0; found 474.0 [M+H]⁺, t_(R)=2.68 min (Method 8).

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid (Compound 289)

Prepared using General Procedure 10. A solution of2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)aceticacid (160 mg, 0.34 mmol), (4-(heptyloxy)phenyl)boronic acid (94 mg, 0.40mmol) and sat aq. NaHCO₃ (930 μl, 0.84 mmol) in ACN (1.5 mL) and THF(1.5 mL) was degassed (N₂ bubbling). PdCl₂(dppf) (262 mg, 0.34 mmol) wasadded and the reaction mixture was heated at 110° C. in a microwavereactor for 50 min. The reaction was partitioned between EA and H₂O. Theorganic layer was dried over MgSO₄, filtered, concentrated and purifiedby chromatography (EA/hexane with 1% AcOH) to afford 113 mg (55%) of2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)aceticacid Compound 289 as a white solid. LCMS-ESI (m/z) calculated forC₃₄H₃₉N₃O₄S: 585.3; found 586.0 [M+H]⁺, t_(R)=3.37 min (Method 9).

(S)—N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxopropan-2-yl)-4-(tert-butyl)benzamide

A solution of Compound 85 (245 mg, 0.413 mmol) in DMF (5 mL) was treatedwith NH₄Cl (180 mg, 3.3 mmol), DIEA (760 μl, 4.1 mmol) and HATU (170 mg,0.4 mmol). After stirring overnight, the reaction mixture was dilutedwith EA (50 mL), washed with aq. 0.5 M HCl (100 mL) and brine (20 mL),then dried over MgSO₄ and concentrated. The residue was re-slurried fromACN (4 mL) to afford 204 mg (77%) of(S)—N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxopropan-2-yl)-4-(tert-butyl)benzamideas a fine white solid. LCMS-ESI (m/z) calculated for C₃₇H₄₄N₄O₃: 592.3;found 593.0 [M+H]⁺, t_(R)=3.43 min (Method 6).

(S)-methyl 3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate

Prepared using General Procedure 7. A solution of (S)-methyl3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride (2.1 g, 8.7 mmol),4-(tert-butyl)benzoic acid (1.6 g, 9.0 mmol) and DIEA (3.5 ml, 18.8mmol) in DMF (20 mL) and DCM (20 mL) was treated with HATU (3.3 g, 8.5mmol). After 1 h, the mixture was poured onto 1M HCl (100 mL) andextracted with EA (3×50 mL). The combined organic extracts were washedsuccessively with 1M HCl (50 mL), water (50 mL) and brine (20 mL), thendried over MgSO₄ and concentrated. The resulting residue was purified bychromatography (EA/hexane) to provide 2.3 g (72%) of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate as whiteneedles. LCMS-ESI (m/z) calculated for C₂₂H₂₇NO: 369.4, found 370.0[M+H]⁺, t_(R)=2.52 min (Method 6).

(S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)butanoate

Prepared using General Procedure 9. A stirred solution of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate (2.30 g, 6.3mmol) in DCM (25 mL) was treated with DIEA (1.4 ml, 7.6 mmol) then1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.5 g, 6.9 mmol). After 18 h, the reaction mixture was diluted with DCM(100 mL), H₂O (50 mL) and NaHCO₃ (75 mL) and stirred for 1 h. Theorganic layer was isolated, washed with NaHCO₃ (100 mL), dried overMgSO₄, concentrated, and purified by chromatography (EA/hexane) toprovide 2.5 g (75%) of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)butanoateas a thick oil. LCMS-ESI (m/z) calculated for C₂₃H₂₆F₃NO₆S: 501.5, found502 [M+H]⁺, t_(R)=3.20 min (Method 6).

(S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoate

To a vial under a N₂ atmosphere were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (530 mg, 2.1mmol), (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)butanoate(810 mg, 1.6 mmol), KOAc (280 mg, 4.8 mmol) and DMSO (14 mL). Thesolution was degassed. Pd(dppf)Cl₂ (59 mg, 0.08 mmol) was added and thesolution was heated to 80° C. for 6 h. The reaction mixture was cooledto room temperature, diluted with EA (100 mL) and washed with sat aq.NaHCO₃ (50 ml) and brine (50 mL). The organic layer was dried overMgSO₄, concentrated and purified by chromatography (EA/hexane) to afford446 mg (57%) of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)as a colorless crystalline solid. LCMS-ESI (m/z) calculated forC₂₈H₃₈BNO₅: 479.4, found 480.3 [M+H]⁺, t_(R)=2.86 min (Method 6).

(S)-methyl4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)-butanoate

Prepared using General Procedure 10. Into a vial were added(S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(390 mg, 0.81 mmol), 5-bromo-2-iodopyrimidine (240 mg, 0.85 mmol),Na₂CO₃ (170 mg, 1.6 mmol), THF (1.5 mL), ACN (1.5 mL) and H₂O (0.75 mL).The solution was degassed and PdCl₂(dppf) (60 mg, 0.08 mmol) was added.The reaction mixture was heated in a microwave reactor at 110° C. for 60min. The sample was cooled, diluted with EA (50 mL), and washed with sataq.NaHCO₃ (30 mL). The organic layers were dried over MgSO₄, filtered,concentrated, and purified by chromatography (EA/hexane) to afford 205mg (49%) of (S)-methyl4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)butanoateas a colourless solid. LCMS-ESI (m/z) calculated for C₂₆H₂₈BrN₃O₃:510.4, found 512.2 [M+H]⁺, t_(R)=2.77 min (Method 6).

(S)-3-(4-(tert-butyl)benzamido)-4-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)butanoicacid (Compound 291)

Prepared using General Procedures 10 and 4. Into a vial wereadded(S)-methyl4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)butanoate(180 mg, 0.35 mmol), (4-(heptyloxy)phenyl)boronic acid (98 mg, 0.41mmol), Na₂CO₃ (73 mg, 0.69 mmol), ACN (1.2 mL), THF (1.2 mL) and H₂O(0.7 mL). The solution was degassed, Pd(dppf)Cl₂ (25 mg, 0.03 mmol) wasadded, and the reaction mixture was heated in a microwave reactor at110° C. for 80 min. The reaction mixture was diluted with EA (50 mL) andwashed with sat aq. NaHCO₃ (30 mL). The organics layer was dried overMgSO₄, concentrated, and purified by chromatography (EA/hexane) toafford 44 mg of methyl ester intermediate. The solid was dissolved inTHF (1 mL) and 1M LiOH (1 mL). The solution was stirred at ambienttemperature for 1 h, concentrated, and 1M HCl (1.5 mL) was added. Thesolid was collected by filtration, washing with water (2×5 mL) andhexane (2×5 mL) to provide 19 mg (9%) of(S)-3-(4-(tert-butyl)benzamido)-4-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)butanoicacid Compound 291 as a colorless solid. LCMS-ESI (m/z) calculated forC₃₈H₄₅N₃O₄: 607.8, found 608.4 [M+H]⁺, t_(R)=10.99 min (Method 10).

5-bromo-2-chloro-4-methoxypyrimidine

To a stirred solution of 5-bromo-2,4-dichloropyrimidine (500 mg, 2.19mmol) in MeOH (5 mL) was added a 30% solution of sodium methoxide (0.40mL, 2.26 mmol). The reaction mixture was stirred at room temperature for2 h then concentrated. The residue was dissolved in water (5 mL) andextracted with EA (3×5 mL). The combined organic layer was washed withbrine, dried over MgSO₄ and concentrated to afford 432 mg (88%) of5-bromo-2-chloro-4-methoxypyrimidine as white solid. LCMS-ESI (m/z)calculated for C₅H₄BrClN₂O: 223.4; found 224.2 [M+H]⁺, t_(R)=7.66 min.(Method 2).

5-bromo-2-iodo-4-methoxypyrimidine

Prepared using General Procedure 16: To a stirred solution of5-bromo-2-chloro-4-methoxypyrimidine (100 mg, 0.447 mmol) in 57% aq. HI(1.0 mL) was added sodium iodide (125 mg, 0.838 mmol). The reactionmixture was stirred at 40° C. for 16 h, cooled, then quenched withNaHCO₃ (5 mL) and extracted with EA (3×5 mL). The combined organics werewashed with brine, dried over MgSO₄ and concentrated to afford 22.0 mg(16%) of 5-bromo-2-iodo-4-methoxypyrimidine as an off-white solid.LCMS-ESI (m/z) calculated for C₅H₄BrIN₂O: 314.9; found 315.9 [M+H]⁺,t_(R)=8.22 min. (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 4.07(s, 3H).

Tert-butyl(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate

Prepared using General Procedure 10: A mixture of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 (30.0 mg, 0.06 mmol), 5-bromo-2-iodo-4-methoxypyrimidine (22.3mg, 0.07 mmol), and sodium carbonate (12.5 mg, 0.12 mmol) inacetonitrile (0.80 mL), THF (0.80 mL) and H₂O (0.40 mL) was degassed for10 min. Pd(dppf)Cl₂:CH₂Cl₂ (5 mg, 0.005 mmol) was added and the reactionmixture heated at 110° C. in a microwave for 30 min. Once cooled, thereaction was diluted with NaHCO₃ (5 mL), extracted with EA (3×5 mL) andthe combined organics dried over MgSO₄ and concentrated. The residue waspurified by column chromatography (EA/hexanes) to afford 20.0 mg (60%)of tert-butyl(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₂₉H₃₄BrN₃O₄: 568.5;found 514.2 [M−tBu+H]⁺, t_(R)=11.0 min. (Method 2).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 10: A mixture of tert-butyl(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate(18.0 mg, 0.031 mmol), (4-(heptyloxy)phenyl)boronic acid (10.0 mg, 0.042mmol) and sodium carbonate (8.97 mg, 0.084 mmol) in acetonitrile (0.80mL), THF (0.80 mL) and H₂O (0.40 mL) was degassed for 10 min.Pd(dppf)Cl₂:CH₂Cl₂ (3.09 mg, 0.003 mmol) was added and the reactionmixture heated at 110° C. in a microwave for 30 min. Once cooled, thereaction was diluted with NaHCO₃ (5 mL) and extracted with EA (3×5 mL).The combined organics were dried over MgSO₄ and concentrated. Theresidue was purified by column chromatography (EA:hexanes) to afford20.0 mg (60%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoateas pale yellow solid. LCMS-ESI (m/z) calculated for C₄₂H₅₃N₃O₅: 679.8;no ion observed, t_(R)=13.83 min. (Method 2).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoicacid (Compound 292)

Prepared using General Procedure 8: A solution of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl-4-methoxypyrimidin-2-yl)phenyl)propanoate(20.0 mg, 0.029 mmol) in DCM (1 mL) was treated with TFA (0.350 mL). Thereaction mixture was stirred at room temperature for 12 h. The solventwas concentrated and the product was purified preparative HPLC to yield15.0 mg (82%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoicacid, Compound 292 as pale yellow solid. LCMS-ESI (m/z) calculated forC₃₈H₄₅N₃O₅: 623.8; no ion observed, t_(R)=12.17 min. (Method 2).

Compound 293 was prepared using tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 and 5-bromo-2-chloro-N,N-dimethylpyrimidin-4-amine using GeneralProcedures 10, 10 and 8 sequentially.

Compound 294 was prepared using tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 and 5-bromo-2-iodo-4-methylpyridine using General Procedures 10,10 and 8 sequentially

5-bromo-2-iodo-4-(trifluoromethyl)pyridine

Prepared using General Procedure 17: To a stirred a solution of5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) inacetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). Thereaction mixture was heated to 40° C. and acetyl chloride (26.0 mg,0.345 mmol) was added. The reaction mixture was stirred at 40° C. for 90min. Once cooled, the reaction was quenched with NaHCO₃ (5 mL) andextracted with EA (3×5 mL). The combined organics were washed with brine(10 mL), dried over MgSO₄ and concentrated to give 80.0 mg (40%) of5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solidwhich was used in the subsequent step without purification. LCMS-ESI(m/z) calculated for C₆H₂BrF₃IN: 351.9; found 352.5 [M+H]⁺, t_(R)=3.91min. (Method 1).

Compound 295 was prepared by employing tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 and 5-bromo-2-iodo-4-(trifluoromethyl)pyridine using GeneralProcedures 10, 10 and 8 sequentially.

(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine(Compound 297)

Prepared using General Procedures 7 and 8: To a solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (185 mg, 0.312 mmol), tert-butyl 2-aminoacetatehydrochloride (52.2 mg, 0.312 mmol), and DIEA (163 μl, 0.935 mmol) inDMF (3 mL) was added HATU (124 mg, 0.327 mmol). The mixture was stirredfor 1 h at room temperature. The crude material was diluted in EA (50mL), washed with saturated aqueous sodium bicarbonate (20 mL) and brine(20 mL). The organic layer was dried over MgSO₄, filtered, and thesolvent removed under reduced pressure. The crude product was purifiedby chromatography (EA/hexanes) to afford the intermediate tert-butylester (110 mg).

The tert-butyl ester was dissolved in DCM (1 mL) and TFA (2 mL) wasadded. The solution was stirred at room temperature for 3 h and thesolvent was removed under reduced pressure. The crude mixture wasdissolved in DMSO (0.8 mL) and precipitated by the addition of water (3mL). The precipitate was filtered, washed with water (3 mL) and hexane(2×2 mL) to yield 58 mg (28%) of(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine,Compound 297 as a colorless solid. LCMS-ESI (m/z) calculated forC₃₉H₄₆N₄O₅: 650.4; found 651.4 [M+H]⁺, t_(R)=10.43 min (Method 10). Thechiral purity was calculated at 92% e.e. (Chiral Method). ¹H NMR (400MHz, DMSO-d6) δ 12.62 (s, 1H), 9.15 (s, 2H), 8.60 (d, J=8.6 Hz, 1H),8.49-8.40 (m, 1H), 8.35-8.25 (m, 2H), 7.84-7.70 (m, 4H), 7.58-7.49 (m,2H), 7.48-7.41 (m, 2H), 7.16-7.02 (m, 2H), 4.90-4.75 (m, 1H), 4.03 (t,J=6.5 Hz, 2H), 3.93-3.75 (m, 2H), 3.25 (dd, J=13.8, 3.8 Hz, 1H), 3.09(dd, J=13.7, 11.2 Hz, 1H), 1.79-1.68 (m, 2H), 1.51-1.21 (m, 17H),0.94-0.80 (m, 3H).

(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid (Compound 298)

Prepared using General Procedures 7 and 8: HATU (116 mg, 0.31 mmol) wasadded to a stirring solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (173 mg, 0.29 mmol), tert-butyl 3-aminopropanoatehydrochloride (53 mg, 0.29 mmol) and DIEA (153 μl, 0.87 mmol) in DMF (3mL). The crude material was diluted in EA (50 mL), washed with saturatedaqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic layerwas dried over MgSO₄, filtered, and the solvent removed under reducedpressure. The crude product was purified by chromatography (EA/hexanes)to afford the intermediate tert-butyl ester (122 mg).

The tert-butyl ester was dissolved in DCM (1 mL) and TFA (2 mL) wasadded. The reaction mixture was stirred at room temperature for 3 h andthe solvent was removed under reduced pressure. The crude mixture wasdissolved in DMSO (0.8 mL) and precipitated by the addition of water (3mL). The precipitate was filtered, washed with water (3 mL) and hexane(2×2 mL) to yield 48 mg (25%) of(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid, Compound 298 as a colorless solid. LCMS-ESI (m/z) calculated forC₄₀H₄₈N₄O₅: 664.4; found 665.4 [M+H]⁺, t_(R)=10.36 min (Method 10). Thechiral purity was calculated at 92% e.e. (Chiral Method, isocratic with40% Solvent A, 60% Solvent B). ¹H NMR (400 MHz, DMSO-d6) δ12.26 (s, 1H),9.15 (s, 2H), 8.51 (d, J=8.5 Hz, 1H), 8.40-8.25 (m, 2H), 8.25-8.14 (m,1H), 7.96-7.65 (m, 4H), 7.65-7.36 (m, 4H), 7.28-6.99 (m, 2H), 4.84-4.64(m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.32-3.24 (m, 2H), 3.17 (dd, J=13.7,4.4 Hz, 1H), 3.06 (dd, J=13.7, 10.4 Hz, 1H), 2.41 (t, J=6.9 Hz, 2H),1.81-1.68 (m, 2H), 1.50-1.20 (m, 17H), 0.88 (t, J=6.7 Hz, 3H).

(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide(Compound 299)

To a solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (78.0 mg, 0.13 mmol), methanesulfonamide (20.0 mg, 0.21mmol), and DMAP (16.1 mg, 0.13 mmol) in DMF (1.5 mL) was added EDC (40.3mg, 0.21 mmol) and the solution stirred overnight at room temperature.The reaction mixture was diluted in EA (50 mL), washed with aqueoussaturated sodium bicarbonate (2×20 mL) and brine (20 mL). The organiclayer was dried over MgSO₄, filtered, and the solvent removed underreduced pressure. The crude product was purified by chromatography(hexane/EA) to afford 36 mg (40%) of(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide,Compound 299 as a colorless solid. LCMS-ESI (m/z) calculated forC₃₈H₄₆N₄O₅S: 670.3; found 671.3 [M+H]⁺, t_(R)=11.01 min (Method 10).

Compounds 300-304 were prepared from(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 using General Procedures 3 or 7 followed by 4 or 8.

Compounds 305-317 were prepared from(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-2-(4-isopropylbenzamido)propanoicacid Compound 94 using General Procedures 3 or 7 followed by 4 or 8.

Compound 318 was prepared from(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(hexyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 225 using General Procedures 7 followed by 8.

(S)-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine(Compound 319)

Prepared using General Procedures 7 and 4: TEA (93 μl, 0.67 mmol) wasadded to a solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 192 (100 mg, 0.167 mmol), methyl 2-aminoacetatehydrochloride (23.03 mg, 0.18 mmol) and HATU (76 mg, 0.20 mmol) in DMF(2 mL). The solution was stirred at room temperature for 18 h. Thereaction mixture was diluted with EA (25 mL) and washed with saturatedaqueous NaHCO₃ (2×25 mL) and 1 M HCl (2×25 mL). The organic phase wasdried over MgSO₄, filtered, and concentrated. The solid was purified bychromatography (EA/hexanes) to afford the methyl ester intermediate as acolorless solid.

The solid was dissolved in THF (3 mL) and 1 M LiOH (333 μl, 0.33 mmol)was added. The resultant yellow solution was stirred at room temperaturefor 1 h. The reaction mixture was acidified to pH 1 using 1M HCl and theTHF removed in vacuo. The residue was suspended in water and the mixturefiltered under vacuum. The solid was azeotroped with MeOH and dried in avacuum oven to afford 48 mg (44%) of(S)-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine,Compound 319 as a yellow solid. LCMS-ESI (m/z) calculated forC₃₇H₄₄N₄O₅S: 656.3; found 657.0 [M+H]⁺, t_(R)=10.34 min (Method 10). Thechiral purity was calculated at 95% e.e. (Chiral Method). ¹H NMR (400MHz, DMSO-d6) δ 12.61 (s, 1H), 9.16 (s, 2H), 8.62 (d, J=8.7 Hz, 1H),8.51-8.41 (m, 1H), 8.36-8.26 (m, 2H), 7.84-7.75 (m, 2H), 7.68 (d, J=3.8Hz, 1H), 7.55-7.43 (m, 2H), 7.14-7.05 (m, 2H), 6.92 (d, J=3.8 Hz, 1H),4.84-4.72 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.89-3.73 (m, 2H), 3.22 (dd,J=13.9, 3.7 Hz, 1H), 3.10-2.96 (m, 1H), 1.78-1.66 (m, 2H), 1.31 (s,17H), 0.94-0.81 (m, 3H).

((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-glutamine(Compound 320)

Prepared using General Procedures 7 and 8: To a stirred solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 192 (250 mg, 0.42 mmol), (S)-tert-butyl2,5-diamino-5-oxopentanoate hydrochloride (109 mg, 0.46 mmol) and TEA(145 μl, 1.04 mmol) in DMF (4 mL) was added HATU (190 mg, 0.50 mmol) andthe reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with EA (50 mL), washed with 1M HCl (50 mL)and brine (100 mL), dried over MgSO₄, and concentrated.

The crude product was dissolved in DCM (5 mL) and TFA (3 mL) was added.After 3 h, toluene (10 mL) was added and the solvent removed. Thecompound was purified by preparative HPLC to afford 78 mg (25%) of((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-glutamine,Compound 320 as a white powder. LCMS-ESI (m/z) calculated forC₄₀H₄₉N₅O₆S: 727.3; found 728.0 [M+H]⁺, t_(R)=10.71 min (Method 10). Thechiral purity was 90% d.e. (Chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ9.15 (s, 2H), 8.56 (d, J=8.6 Hz, 1H), 8.42-8.34 (m, 1H), 8.34-8.27 (m,2H), 7.84-7.75 (m, 2H), 7.66 (d, J=3.9 Hz, 1H), 7.54-7.48 (m, 2H), 7.32(s, 1H), 7.12-7.04 (m, 2H), 6.90 (d, J=3.8 Hz, 1H), 6.77 (s, 1H),4.81-4.65 (m, 1H), 4.19-4.11 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.20 (dd,J=14.1, 3.5 Hz, 1H), 3.07-2.96 (m, 1H), 2.24-2.09 (m, 2H), 2.06-1.93 (M,1H), 1.90-1.79 (m, 1H), 1.78-1.68 (m, 2H), 1.47-1.20 (m, 17H), 0.93-0.82(m, 3H).

Compounds 321-326 were prepared from Compound 192 using GeneralProcedures 3 or 7 followed by 4 or 8.

(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl) phenyl) propanoic acid (INT-22)

Prepared using General Procedure 8. To a stirred solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoate INT-8 (6.4 g, 10.26 mmol) in DCM (30 mL) was addedTFA (20 mL) and the mixture was stirred at room temperature for 3 h.Toluene (50 mL then 2×30 mL) was added and the solvent as removed undervacuum. The material was sonicated in DCM (20 mL) and acetonitrile (30mL) was added. The DCM was partially removed under a flow of air until aprecipitate began to appear. The suspension was stirred for a further 2h and the yellow solid was isolated by filtration and washed withadditional iso-hexanes (100 mL). The solid was dried under suction thenat under vacuum at 40° C. overnight to afford 5.5 g (90%)(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoic acid INT-22 as a yellow solid. LCMS-ESI (m/z)calculated for C₃₄H₃₇N₃O₅: 567.3; found 568.3 [M+H]⁺, t_(R)=10.11 min(Method 10).

Tert-butyl((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(INT-23)

Prepared using General Procedure 7. To a stirred solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid (1000 mg, 1.762 mmol) and (R)-tert-butyl 2-aminopropanoate HCl (352mg, 1.938 mmol) in DMF (8 mL). The solution was cooled to 0° C. and TEA(737 μl, 5.28 mmol) was added. To this mixture was slowly added HATU(804 mg, 2.114 mmol) over 5 mins then the reaction mixture was allowedto warm to room temperature. The reaction mixture was diluted with EA(150 mL) and washed with 1M HCl (100 mL) then brine (100 mL). Theorganic layer was isolated and dried over MgSO₄. The solvents wereremoved to give a white solid and ACN (50 mL) was added and thesuspension was sonicated. The fine suspension was stirred for 30 minsthen filtered and washed with iso-hexanes to afford 881 mg (70.5%) oftert-butyl((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninateINT-23 as a white powder. LCMS-ESI (m/z) calculated for C₄₁H₅₀N₄O₆:694.4; no m/z observed, t_(R)=3.39 min (Method 11). The chiral puritywas calculated at >99% e.e. (Chiral Method).

Tert-butyl((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(INT-24)

Prepared using General Procedure 18: To a stirred solution of tert-butyl((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(860 mg, 1.238 mmol) in THF (30 mL) was added palladium on carbon (10 wt%) as a slurry in EtOH (4 mL). To this mixture was added acetic acid (1mL) and the reaction mixture was hydrogenated at 4 bar pressure at roomtemperature. The reaction mixture was diluted with THF (50 mL) andfiltered through Celite. The crude product was loaded onto a column in5% AcOH in MeOH/THF. The column was washed with MeOH/THF/DCM and thenthe product was eluted with 0.7 M ammonia in MeOH/THF/DCM. The resultantmixture was concentrated in vacuo to afford 565 mg (77%) of tert-butyl((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninateINT-24 as a yellow solid. LCMS-ESI (m/z) calculated for C₃₃H₄₄N₄O₄:560.3; no m/z observed, t_(R)=2.61 min (Method 11).

Tert-butyl((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate

Prepared using General Procedure 7. To a stirred solution of tert-butyl((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(418 mg, 0.75 mmol), 5-(tert-butyl)thiophene-2-carboxylic acid (137 mg,0.75 mmol) in DMF (8 mL) was added TEA (208 μl, 1.49 mmol). The mixturewas cooled to 0° C. and HATU (298 mg, 0.78 mmol) was added in 2 portionsover 5 mins. The mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with EA (150 mL) and washed with saturatedaqueous NaHCO₃ (100 mL), IN HCl (100 mL), and brine (100 mL). Theorganic layer was dried over MgSO₄ then concentrated. The crude productwas purified by chromatography 0-30% ACN in DCM to afford 382 mg (69%)of tert-butyl((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate as a white solid. LCMS-ESI(m/z) calculated for C₄₂H₅₄N₄O₅S: 726.4; no m/z observed, t_(R)=3.47 min(Method 11).

((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine(Compound 327)

Prepared using General Procedure 8. To a stirred solution of tert-butyl((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (375 mg, 0.495 mmol) in DCM (8 mL) was added TFA(4 mL) and the mixture was stirred at room temperature for 3 h. Thereaction mixture was azetroped with toluene (2×30 mL) to give a viscousoily solid. DMSO (5 mL) was added and the solution was sonicated. Tothis solution was added water (60 mL) and the mixture was sonicated for5 mins then stirred at room temperature for 20 mins. The white solid wasisolated by filtration and washed with additional water (20 mL) andisohexanes (30 mL). The material was dried under vacuum, suspended inACN (20 mL), then diluted with diethyl ether (30 mL) and stirred for 20mins. The suspension was filtered and the wet solid was dried undervacuum to give 189.3 mg (55%) of((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine Compound 327 as a white powder. LCMS-ESI (m/z)calculated for C₃₈H₄₆N₄O₅S: 670.3; found 671.0 [M+H]⁺, t_(R)=13.32 min(Method 10). The chiral purity was calculated at >99% e.e. (ChiralMethod). ¹NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.16 (s, 2H), 8.56 (d,J=8.8 Hz, 1H), 8.48 (d, J=7.4 Hz, 1H), 8.35-8.26 (m, 2H), 7.84-7.76 (m,2H), 7.70 (d, J=3.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.13-7.05 (m, 2H), 6.92(d, J=3.8 Hz, 1H), 4.86-4.77 (m, 1H), 4.29-4.18 (m, 1H), 4.03 (t, J=6.5Hz, 2H), 3.20-3.10 (m, 1H), 3.08-2.94 (m, 1H), 1.80-1.68 (m, 2H),1.51-1.22 (m, 20H), 0.94-0.83 (m, 3H).

(S)-tert-butyl1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate(INT-25)

Prepared using General Procedure 7. A stirred solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid (419 mg, 0.738 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate HCl(153 mg, 0.738 mmol) and TEA (257 μl, 1.845 mmol) in DMF (6 mL) wascooled to 0° C. and HATU (295 mg, 0.775 mmol) was slowly added over 5minutes. The reaction was stirred at room temperature for 2 h, thendiluted with 1M citric acid (30 mL) and iso-hexanes (20 mL). EA (100 mL)was added and the organic layer was isolated, washed with brine (100mL), dried with MgSO₄. The solvent was removed and the crude product waspurified by chromatography 0-20% ACN in DCM to afford 436 mg (81%) of(S)-tert-butyl1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate INT-25 as a viscous oil. LCMS-ESI (m/z)calculated for C₄₃H₅₂N₄O₆: 720.4; no m/z observed, t_(R)=11.45 min(Method 10).

(S)-tert-butyl1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate(INT-26)

Prepared using General Procedure 18: A solution of (S)-tert-butyl1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (436 mg, 0.6 mmol) in THF (25 mL) washydrogenated in the H-Cube using a 10% Pd/C CatCart at 60° C. (Fullhydrogen, 1 mL/min). The reaction mixture was passed over the catalyst asecond time at 65° C. The solvent was removed to give 307 mg (83%) of(S)-tert-butyl1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylateINT-26 as a white powder. LCMS-ESI (m/z) calculated for C₃₅H₄₆N₄O₄:586.4; found 587.4 [M+H]⁺, t_(R)=6.99 min (Method 10).

(S)-tert-butyl1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate

Prepared using General Procedure 7: A stirred solution of (S)-tert-butyl1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate(306 mg, 0.522 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (106mg, 0.574 mmol) in DMF (6 mL) was added TEA (145 μl, 1.043 mmol), cooledto 0° C., then HATU (218 mg, 0.574 mmol) was slowly added over 5minutes. The reaction was stirred at room temperature for 2 h, thendiluted with EA (70 mL), washed with saturated aqueous NaHCO₃ (70 mL)and brine (100 mL). The solvent was dried over MgSO₄ and removed. Thecrude product was purified by chromatography 0-30% ACN in DCM to afford363 mg (92%) of (S)-tert-butyl1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate as a sticky solid. LCMS-ESI (m/z)calculated for C₄₄H₅₆N₄O₅S: 752.4; no m/z observed, t_(R)=11.99 min(Method 10).

(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylicacid (Compound 328)

Prepared using General Procedure 8. To a stirred solution of(S)-tert-butyl1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (350 mg, 0.465 mmol) in DCM (5 mL)was added TFA (5 mL) and stirred at room temperature for 2 h. Thereaction mixture was diluted with toluene (10 mL) and solvent removed.The residue was dissolved in EA (50 mL), THF (5 mL) and acetone (10 mL)and washed with a mixture of saturated aqueous NaHCO₃ (10 mL) and brine(40 mL). The aqueous layer was removed and acetic acid (5 mL) was added.The organic layer was washed with brine (50 mL) and dried over MgSO₄.The solvent was removed and residual acetic acid was removed under highvacuum overnight. The material was dissolved in DCM (5 mL) and ACN (5mL) was added. The material was stirred under a flow of air for 1 hourand the suspension was filtered and the solid washed with additional ACN(5 mL) and iso-hexanes (20 mL) to give 134 mg (41%) of(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylicacid Compound 328 as a yellow powder. LCMS-ESI (m/z) calculated forC₄₀H₄₈N₄O₅S: 696.3; found 697.3 [M+H]⁺, t_(R)=10.59 min (Method 10). Thechiral purity was calculated at >93% e.e. (Chiral Method). ¹H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 9.17 (s, 2H), 8.74 (d, J=8.3 Hz, 1H),8.38-8.27 (m, 2H), 7.86-7.76 (m, 2H), 7.71 (d, J=3.9 Hz, 1H), 7.57-7.48(m, 2H), 7.14-7.02 (m, 2H), 6.92 (d, J=3.9 Hz, 1H), 4.94-4.86 (m, 1H),4.33-4.27 (m, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.86-3.74 (m, 1H), 3.69-3.59(m, 1H), 3.19-3.01 (m, 2H), 2.24-2.13 (m, 1H), 2.01-1.84 (m, 3H),1.80-1.68 (m, 2H), 1.52-1.23 (m, 17H), 0.93-0.85 (m, 3H).

Compounds 329-350 were prepared from Compound 192 using GeneralProcedures 3 or 7 followed by 4 or 8.

Compounds 351-368 were prepared from Compound 165 using GeneralProcedures 7 followed by 4 or 8.

Compound 369 was prepared from Compound 139 using General Procedures 7followed by 8.

Compound 370 was prepared from Compound 167 using General Procedures 7followed by 8.

Compound 371 was prepared from Compound 142 using General Procedures 7followed by 8.

Compound 372 was prepared from Compound 143 using General Procedures 7followed by 8.

Compound 373 was prepared from Compound 182 using General Procedures 7followed by 8.

Compounds 374-379 were prepared from Compound 193 using GeneralProcedures 3 or 7 followed by 4 or 8.

Compound 380 was prepared from Compound 191 using General Procedures 7followed by 8.

(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide(Compound 381)

TEA (32.1 μl, 0.23 mmol) was added to a suspension of(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycineCompound 297 (75.0 mg, 0.11 mmol), methanesulfonamide (12.1 mg, 0.13mmol), HATU (52.6 mg, 0.14 mmol) and DMAP (1.41 mg, 0.01 mmol) in DCM (2mL). The resultant yellow suspension was stirred at room temperature for3 h. The reaction mixture was washed with saturated aqueous NaHCO₃ (2mL) and the mixture passed through a phase separation cartridge. Theorganic phase was concentrated in vacuo to afford a yellow solid. Thecrude product was purified by chromatography (EA/1% AcOH in hexanes) toafford 9 mg (11%)(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide,Compound 381 as a yellow solid. LCMS-ESI (m/z) calculated forC₄₀H₄₉N₅O₆S: 727.3; found 728.0 [M+H]⁺, t_(R)=10.51 min (Method 10).

Compounds 382-390 were prepared from Compound 192 using the appropriatecombination of General Procedures 4, 7, and 8 as needed.

Ethyl2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

To a stirred solution of ethyl 2-((diphenylmethylene)amino)acetate (300mg, 1.12 mmol) in anhydrous THF (3 mL) at −78° C. was added 0.5 M KHMDSin toluene (2.46 mL, 1.23 mmol). After stirring for 15 min,2-(4-(bromomethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(353 mg, 1.12 mmol) was added. The reaction mixture was stirred at −78°C. for 3 h and warmed to −20° C. To the mixture was added 6 NHydrochloric acid (0.5 mL) and the mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with water (5 mL) and 1 NHCl (5 mL) and then extracted with diethyl ether. The aqueous layer wasbasified with 1N NaOH and then extracted with EtOAc (3×10 mL). Thecombined organic extract was washed with water, brine and then driedover MgSO₄. Filtration and concentration gave 177 mg (46%) of ethyl2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoatewhich was used in the next step without purification. LCMS-ESI (m/z)calculated for C₁₇H₂₅BFNO₄: 337.2; found 338.2 [M+H]⁺, t_(R)=2.78 min(Method 1).

Compound 391 was prepared using ethyl2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateand 5-(tert-butyl)thiophene-2-carbonyl chloride using General Procedure3 followed by treatment with 5-(4-(tert-butyl)phenyl)-2-iodopyrimidineand General procedure 10.

Compounds 392-396 were prepared from Compound 192 using, as needed, theappropriate combination of General Procedures 4, 7, and 8.

(S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylicacid

Prepared using General Procedure 10. Into an oven-dried vial containinglithium formate (58 mg (1.1 mmol) in DMF (5 mL) were added DIEA (400 μL,2.2 mmol) and acetic anhydride (210 μL, 2.2 mmol). After stirring for 1h, the reaction mixture was degassed by N₂ bubbling. A second, degassedsolution containing (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate,INT-14 (200 mg, 0.4 mmol) and PdCl₂(dppf) (27 mg, 0.04 mmol) in DMF (5mL) was added via cannula. The resulting mixture was heated for 1 h at120° C. in a microwave reactor. The reaction mixture was diluted with10% citric acid and extracted with EA. The organic extract was dried(Na₂SO₄), concentrated, and purified by chromatography (EA/hexane) toprovide 166 mg (88%) of(S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylicacid as a brown solid. LCMS-ESI (m/z) calculated for C₂₉H₃₃BN₃O₅: 503.6;found 504.2 [M+H]⁺, t_(R)=3.87 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ9.24 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.75 (t, J=11.9 Hz, 2H), 7.45 (d,J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 6.91 (t, J=11.5 Hz, 1H), 5.12(dd, J=12.9, 5.5 Hz, 1H), 3.32 (qd, J=13.8, 5.4 Hz, 2H), 1.50 (s, 9H),1.29 (d, J=29.8 Hz, 9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)pyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 7. Into a stirring solution of(S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylicacid (50 mg, 0.10 mmol) in DCM (2 mL) were added EDC (34 mg, 0.20 mmol),DMAP (3 mg, 0.02 mmol) and heptanehydrazide (16 mg, 0.11 mmol). After 18h, the reaction mixture was diluted with NaHCO₃ and extracted with DCM(2×). The organic layers were combined, dried (Na₂SO₄), concentrated andpurified by chromatography (EA/Hexane) to provide 38 mg (61%) oftert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)pyrimidin-2-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₆H₄₇BN₅O₅: 629.8; no m/z observed,t_(R)=3.84 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 2H), 8.42(d, J=8.2 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.34(d, J=8.2 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 5.01 (dd, J=12.6, 5.8 Hz,1H), 3.41-3.20 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 1.81-1.61 (m, 2H), 1.59(d, J=14.0 Hz, 2H), 1.45 (s, 4H), 1.42-1.22 (m, 18H), 0.88 (t, J=6.8 Hz,3H).

Tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1, 3,4-thiadiazol-2-yl)pyrimidin-2-yl)phenyl)propanoate

To a solution of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)pyrimidin-2-yl)phenyl)propanoate(38 mg, 0.06 mmol) in THF (1.5 mL) was added2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (24mg, 0.06 mmol). After 1.5 h, the reaction mixture was concentrated andpurified by preparative HPLC to provide 10 mg (27%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl) phenyl) propanoate. LCMS-ESI (m/z) calculated forC₃₆H₄₅N₅O₅S: 627.9; no m/z observed, t_(R)=3.89 min (Method 1). ¹H NMR(400 MHz, CDCl₃) δ 9.29 (s, 2H), 8.44 (d, J=8.2 Hz, 2H), 7.75-7.66 (m,2H), 7.50-7.41 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 6.68 (d, J=7.3 Hz, 1H),5.02 (dd, J=12.7, 5.6 Hz, 1H), 3.33 (qd, J=13.8, 5.5 Hz, 2H), 3.26-3.15(m, 2H), 1.87 (dt, J=15.3, 7.6 Hz, 2H), 1.46 (d, J=5.1 Hz, 10H),1.41-1.23 (m, 14H), 0.96-0.85 (m, 3H).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1, 3,4-thiadiazol-2-yl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 397)

Prepared using General Procedure 8 from tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl) phenyl) propanoate. LCMS-ESI (m/z) calculated forC₃₂H₃₇N₅O₃S: 571.4; found 571.7 [M+H]⁺, t_(R)=10.66 min (Method 2). ¹HNMR (400 MHz, CDCl₃) δ 9.30 (d, J=2.6 Hz, 2H), 8.48 (d, J=8.2 Hz, 2H),7.67 (d, J=8.4 Hz, 2H), 7.43 (dd, J=13.7, 8.3 Hz, 4H), 6.61 (d, J=6.8Hz, 1H), 5.20-5.04 (m, 1H), 3.45 (ddd, J=36.2, 13.9, 5.6 Hz, 2H), 3.20(t, J=7.6 Hz, 2H), 1.95-1.75 (m, 2H), 1.54-1.36 (m, 2H), 1.39-1.19 (m,13H), 0.91 (t, J=7.0 Hz, 3H).

(R)-tert-butyl2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate

Prepared using General Procedure 7. A stirred solution of (R)-tert-butyl2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate(122 mg, 0.218 mmol), 4-(tert-butyl)benzoic acid (38.8 mg, 0.218 mmol)and TEA (60.7 μl, 0.435 mmol) in DMF (4 mL) was cooled to 0° C. and HATU(87 mg, 0.228 mmol) was slowly added over 5 minutes. The reaction wasstirred at room temperature for 2 h, then diluted with EA (100 mL),washed with saturated aqueous NaHCO₃ (100 mL) and brine (100 mL). Thesolvent was dried over MgSO₄ and removed. The crude product was purifiedby chromatography 0-30% ACN in DCM to afford 123 mg (78%) of(R)-tert-butyl2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₄₄H₅₆N₄O₅: 720.4; nom/z observed, t_(R)=3.47 min (Method 11).

(R)-2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoic acid (Compound 398)

Prepared using General Procedure 8. To a stirred solution of(R)-tert-butyl2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate(120 mg, 0.166 mmol) in DCM (4 mL) was added TFA (3 mL) and stirred for2 h. The reaction mixture was diluted with toluene (15 mL) and solventremoved. DMSO (3 mL) was added and the solution was sonicated. Thissolution was added to vigorously stirring water (30 mL) and the whitesolid was isolated by filtration and washed with additional ACN (10 mL).The material was dried under high vacuum for 24 h to afford 75 mg (66%)of(R)-2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid Compound 398 as a white powder. LCMS-ESI (m/z) calculated forC₄₀H₄₈N₄O₅: 664.4; found 665.0 [M+H]⁺, t_(R)=12.33 min (Method 10). Thechiral purity was calculated at >99% e.e. (Chiral Method). ¹H NMR (400MHz, DMSO-d6) δ 12.64 (s, 1H), 9.15 (s, 2H), 8.52 (d, J=8.7 Hz, 1H),8.45 (d, J=7.4 Hz, 1H), 8.35-8.20 (m, 2H), 7.85-7.68 (m, 4H), 7.56-7.50(m, 2H), 7.49-7.39 (m, 2H), 7.14-7.03 (m, 2H), 4.93-4.80 (m, 1H),4.38-4.17 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.22-3.12 (m, 1H), 3.12-3.02(m, 1H), 1.81-1.67 (m, 2H), 1.53-1.24 (m, 20H), 0.95-0.80 (m, 3H).

Compounds 399-409 were prepared using, as needed, the appropriatecombination of General Procedures 4, 7, 8, and 18.

(S)-4-amino-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)butanoic acid (Compound 410)

Prepared using General Procedures 7, 4, and 8: A stirring solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 192 (25 mg, 0.042 mmol), (S)-methyl2-amino-4-((tert-butoxycarbonyl)amino)butanoate hydrochloride (12 mg,0.042 mmol), and TEA (0.015 mL, 0.105 mmol) at 0° C. was treated withHATU (17 mg, 0.046 mmol) in DMF (1 mL). The solution was stirred at roomtemperature for 18 h. The reaction mixture was diluted with DCM (5 mL)and washed with saturated aqueous NaHCO₃ (5 mL), water (5 mL), and brine(5 mL). The organic phase was dried over MgSO₄, filtered, andconcentrated to afford the methyl ester intermediate. The ester wasdissolved in THF (2 mL) and MeOH (1 mL) and 1 N aqueous NaOH (0.1 ml,0.1 mmol) was added. The solution was stirred at 60° C. for 5 h. Thereaction mixture was concentrated then dissolved in DCM (0.5 mL) andtreated with 1N HCl in ether (0.42 mL, 0.42 mmol). The reaction wasstirred at 27° C. for 18 h. The compound was purified by preparativeHPLC to afford 21 mg (60.0%) of(S)-4-amino-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)butanoicacid as the trifluoroacetate salt. LCMS-ESI (m/z) calculated forC₃₉H₄₉N₅O₅S: 699.4; found 700.3 [M+H]⁺, t_(R)=9.24 min (Method 12). ¹HNMR (400 MHz, DMSO) δ 12.95 (s, 1H), 9.15 (s, 2H), 8.63-8.55 (m, 2H),8.32 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.76-7.63 (m, 4H), 7.51(d, J=8.2 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 6.91 (d, J=3.7 Hz, 1H),4.87-4.66 (m, 1H), 4.50-4.31 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.23-3.12(m, 1H), 3.12-3.00 (m, 1H), 2.95-2.77 (m, 2H), 2.18-2.02 (m, 1H),2.02-1.84 (m, 1H), 1.83-1.64 (m, 2H), 1.50-1.38 (m, 2H), 1.38-1.14 (m,15H), 0.87 (t, J=6.7 Hz, 3H).

Compounds 411-418 were prepared using, as needed, the appropriatecombination of General Procedures 4, 7, 8, and 18.

Compounds 419-423 and 435 were prepared in a similar fashion to Compound381.

Compounds 424-433 were prepared using, as needed, the appropriatecombination of General Procedures 4, 7, 8, and 18.

Compound 434 was prepared from Compound 422 using General Procedure 4.

Compounds 436-440 were prepared using, as needed, the appropriatecombination of General Procedures 4, 7, 8, and 18.

Compounds 441 and 442 were prepared from Compound 192 using GeneralProcedures 3 and 8.

Compound 443 was prepared from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateusing General Procedures 12 then 8.

Compounds 444-455 were prepared using, as needed, the appropriatecombination of General Procedures 4, 7, 8, and 18.

Compounds 456-458 were prepared from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateusing General Procedures 12 then 8.

Compounds 459-464 were prepared from Compound 192 using, as needed, theappropriate combination of General Procedures 4, 7, and 8.

Compounds 465-466 were prepared from Compound 85 using, as needed, theappropriate combination of General Procedures 4, 7, and 8.

2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-(1H-1,2, 4-triazol-1-yl)propanoic acid (Compound 467)

Prepared using General Procedure 7 and then 4.(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid (90 mg, 0.152 mmol) and (S)-methyl2-amino-3-(1H-1,2,4-triazol-1-yl)propanoate (25.8 mg, 0.152 mmol) in DMF(2.5 mL) was added TEA (52.8 μl, 0.379 mmol) and then cooled to 0° C. Tothis mixture was added HATU (57.6 mg, 0.152 mmol) and left at roomtemperature for 2 h. The reaction mixture was quenched by the additionof 0.1 M Citric acid (aq. 15 mL) and the solid precipitated was allowedto slurry for 30 mins. The solid was filtered, washed with water (10mL), isohexanes (10 mL) and then dried. Then the solid was dissolved inmixture of THF (4 mL) and MeOH (2 mL). To this solution was added 2M aq.NaOH (380 μL, 0.76 mmol) and the mixture was stirred vigorously at roomtemperature for 1 h. The reaction mixture was diluted with 0.1 M aq.citric acid (20 mL) and stirred for 1 h. The solid formed was filteredand washed with water (10 mL) and isohexanes (10 mL). The crude productwas purified by column chromatography (0-20% MeOH in EA) to afford 12 mg(11%) of2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-(1H-1,2,4-triazol-1-yl)propanoicacid as a white powder. LCMS-ESI (m/z) calculated for C₄₂H₄₉N₇O₅: 731.9;no m/z observed, t_(R)=9.75 min (Method 10). ¹H NMR (400 MHz, DMSO-d6)δ13.21 (s, 1H), 9.20 (s, 2H), 8.70 (d, J 8.1 Hz, 0.5H), 8.60 (dd, J 8.4,4.6 Hz, 1H), 8.56 (d, J=7.8 Hz, 0.5H), 8.52 (d, J=7.1 Hz, 1H), 8.37-8.34(m, 2H), 8.01 (d, J=6.9 Hz, 1H), 7.85-7.82 (m, 2H), 7.80-7.78 (m, 2H),7.56-7.49 (m, 4H), 7.14 (d, J=8.9 Hz, 2H), 4.87-4.74 (m, 2H), 4.71-4.55(m, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.24-2.97 (m, 2H), 1.82-1.75 (m, 2H),1.51-1.29 (m, 17H), 0.95-0.91 (m, 3H).

Compounds 468 and 469 were prepared from Compound 85 using, as needed,the appropriate combination of General Procedures 4, 7, and 8.

Compound 470 was prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 using General Procedures 7 and 8.

(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoicacid (INT-27)

Prepared using General Procedure 8. LCMS-ESI (m/z) calculated forC₂₄H₂₄BrN₃O₃: 482.3; found 481.1 [M−H]⁺, t_(R)=2.6 min (Method 15), and98.7% e.e. (Chiral Method, isocratic with 2% Solvent A, 98% Solvent B).¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 2H), 8.32 (d, J=8.3 Hz, 2H), 7.64 (d,J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 6.64 (d,J=6.9 Hz, 1H), 5.16 (dd, J=12.7, 5.7 Hz, 1H), 3.42 (ddd, J=38.8, 14.0,5.7 Hz, 2H), 1.32 (s, 9H).

Tert-butyl(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoate(INT-28)

Prepared using General Procedure 7. A stirring solution of β-alaninetert-butyl ester hydrochloride (4.9 g, 27.4 mmol),(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoicacid (12.0 g, 24.9 mmol) and DIEA (11.1 mL, 62.0 mmol) in DMF (200 mL)was cooled to 0° C. A solution of HATU (9.9 g, 26.1 mmol) in DMF (75 mL)was added dropwise over 20 min. The reaction mixture was allowed to warmto room temperature over 2 h, then diluted with EA and washed withNaHCO₃ (sat aq). The aqueous fraction was back-extracted with EA. Thecombined organic fractions were dried (Na₂SO₄) then concentrated ontocelite and purified by column chromatography (EA/hexane) to provide 11 g(65%) of tert-butyl(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoateINT-28. LCMS-ESI (m/z) calculated for C₃₁H₃₇BrN₄O₄; 609.6; found 610.2[M+H]⁺, t_(R)=3.99 min (Method 15), and 87.1% e.e. (Chiral Method,isocratic with 20% Solvent A, 80% Solvent B). ¹H NMR (400 MHz, CDCl₃)δ8.80 (s, 2H), 8.32 (t, J=6.5 Hz, 2H), 7.74-7.62 (m, 2H), 7.41 (d, J=8.5Hz, 2H), 7.35 (t, J=7.9 Hz, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.53 (t, J=5.9Hz, 1H), 4.93-4.81 (m, 1H), 3.52-3.34 (m, 2H), 3.34-3.14 (m, 2H),2.46-2.24 (m, 2H), 1.34 (d, J=5.2 Hz, 9H), 1.31 (d, J=5.2 Hz, 9H).

Tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate(INT-29)

Prepared using General Procedure 10 from tert-butyl(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoateand 4-hydroxyphenyl boronic acid. LCMS-ESI (m/z) calculated forC₃₇H₄₂BN₄O₅: 622.8; found 621.3 [M−H]⁺, t_(R)=3.53 min. (Method 15), and80.1% e.e. (Chiral Method, isocratic with 20% Solvent A, 80% Solvent B).¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 2H), 8.42 (d, J=8.0 Hz, 2H), 7.70 (d,J=8.2 Hz, 2H), 7.56-7.32 (m, 6H), 6.95 (d, J=8.2 Hz, 2H), 6.82 (d, J=7.6Hz, 1H), 6.35 (s, 1H), 4.88 (d, J=6.9 Hz, 1H), 3.46 (s, 2H), 3.39-3.12(m, 2H), 2.48-2.15 (m, 2H), 1.36 (s, 9H), 1.33 (s, 9H).

Compound 471 was prepared from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateusing General Procedures 12 then 8. Tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-((5-methylhexyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate

Prepared using General Procedure 12 from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateand 1-bromo-5-methyl hexane. LCMS-ESI (m/z) calculated for C₄₄H₅₆N₄O₅:720.9; found 721.4 [M+H]⁺, t_(R)=5.39 min. (Method 16).

(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-((5-methylhexyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid (Compound 472)

Prepared using General Procedure 8 from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-((5-methylhexyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate.LCMS-ESI (m/z) calculated for C₄₀H₄₅N₄O₅: 664.9; found 664.8 [M+H]⁺,t_(R)=10.32 min. (Method 14).

Compound 473 was prepared from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-propanoateusing General Procedures 12 then 8.

Tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(2-cyclohexylethoxy)phenyl)-pyrimidin-2-yl)phenyl)propanamido)propanoate

Prepared using General Procedure 12 from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateand (2-bromoethyl)cyclohexane. LCMS-ESI (m/z) calculated for C₄₅H₅₆N₄O₅:732.9; found 733.5 [M+H]⁺, t_(R)=5.59 min. (Method 16).

(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(2-cyclohexylethoxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid (Compound 474)

Prepared using General Procedure 8 from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(2-cyclohexylethoxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate.LCMS-ESI (m/z) calculated for C₄₁H₄₈N₄O₅: 676.9 found 677.4 [M+H]⁺,t_(R)=10.61 min. (Method 14).

Compounds 475 and 476 were prepared from Compound 85 using GeneralProcedures 7, 4, then 8.

4-Benzyl 1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate(INT-30)

Prepared using General Procedure 7: To a stirred solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (594 mg, 1.00 mmol), L-aspartic acid β-benzyl esterα-tert-butyl ester hydrochloride (398.4 mg, 1.20 mmol) in DMF (6 mL) wasadded DIEA (554 μl, 3.00 mmol). The mixture was cooled to 0° C. and HATU(418 mg, 1.10 mmol) in DMF (4 mL) was added over 5 mins. The mixture wasstirred at 0° C. for 1 h. The reaction mixture was added to water (200mL) and the precipitate was filtered. The precipitate was dissolved inDCM (20 mL), dried over MgSO₄, and concentrated. The crude product waspurified by chromatography 0-100% EA in hexane to afford 751 mg (88%) of4-benzyl 1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartateINT-30 as a white solid. LCMS-ESI (m/z) calculated for C₅₂H₆₂N₄O₇:854.5; found 855.5 [M+H]⁺, t_(R)=6.22 min (Method 16).

(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoicacid (INT-31)

Prepared using General Procedures 18: To 4-benzyl 1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate(50 mg, 0.058 mmol) in THF (2 mL) was added 10% Pd/C (10 mg). Thereaction vessel was flushed with hydrogen gas and the reaction wasstirred vigorously under hydrogen for 2 h at room temperature. Thereaction mixture was filtered to remove the catalyst and the solvent wasremoved to give 38 mg (86%) of(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoicacid INT-31 as a white solid. LCMS-ESI (m/z) calculated for C₄₅H₅₆N₄O₇:764.4; found 765.4 [M+H]⁺, t_(R)=4.24 min (Method 16).

N²—((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-N⁴-methyl-L-asparagine(Compound 477)

Prepared using General Procedure 7 and 8: To a stirred solution of(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoicacid (19 mg, 0.025 mmol), methylamine (40 wt % in water, 5.8 μL, 0.075mmol) in DMF (0.25 mL) was added DIEA (13.8 μl, 0.075 mmol). The mixturewas cooled to 0° C. and HATU (19 mg, 0.05 mmol) was added. The mixturewas stirred at room temperature for 18 h. The reaction mixture was addedto water (2 mL) and the precipitate was filtered. The precipitate wasdissolved in DCM (2 mL), dried over MgSO₄, and concentrated. The crudeester was dissolved in DCM (1 mL) and TFA (0.2 mL) was added. Thereaction was stirred overnight. The solvent was removed and the crudematerial was purified by preparative HPLC to afford 5 mg (25%) ofN²-((s)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-N⁴⁻methyl-L-asparagine.LCMS-ESI (m/z) calculated for C₄₂H₅₁N₅O₆; 721.4; found 722.4 [M+H}⁺,t_(R)=8.67 min (Method 14). ¹H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 9.14(s, 2H), 8.53 (d, J=8.5 Hz, 1H), 8.36 (d, J=7.9 Hz, 1H), 8.29 (d, J=8.2Hz, 2H), 7.86 (d, J=4.6 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.3Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.8Hz, 2H), 4.89-4.73 (m, 1H), 4.66-4.53 (m, 1H), 4.03 (t, J=6.5 Hz, 3H),3.26-3.18 (m, 1H), 3.11-3.00 (m, 1H), 2.64-2.53 (m, 5H), 1.80-1.67 (m,2H), 1.51-1.38 (m, 2H), 1.38-1.21 (m, 15H), 0.87 (t, J=6.8 Hz, 3H).

Compounds 478-487 were prepared from(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoicacid using General Procedures 7 and 8.

Compound 488 was prepared from Compound 85 using General Procedures 7and 4.

Compounds 489 and 490 were prepared from tert-butyl(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)propanoateusing General Procedures 12 then 8.

Compound 491 was prepared from Compound 85 using General Procedures 7then 4.

Tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninate(INT-32)

To a stirring solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoicacid INT-27 (1.50 g, 3.10 mmol) in DMF (15 mL) were added tert-butylD-alaninate (680.0 mg, 3.73 mmol) and Et₃N (802.3 mg, 6.2 mmol). Thereaction was stirred for 1 hour at 0° C. and then HATU (877.5 mg, 3.37mmol) in 2 mL DMF was added. The reaction was stirred for 1 hour at 0°C. and then warmed to room temperature with stirring for 18 hours. Thereaction solution was extracted with aqueous NaHCO₃ (3×20 mL). Thecombined organics were dried over MgSO₄ and evaporated. The crudeproduct was purified by column chromatography (50%) EA in hexanes) toafford 1.44 g (76%) of tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninateINT-32 as a solid powder. LCMS-ESI (m/z) calculated for C₃₁H₃₇BrN₄O₄:609.6; found 610.2 [M+H]⁺, t_(R)=4.05 min. (Method 16). ¹H NMR (400 MHz,DMSO) δ 9.03 (s, 2H), 8.49 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H),8.24 (d, J=8.2 Hz, 2H), 7.73 (t, J=7.4 Hz, 2H), 7.54-7.37 (m, 4H), 4.85(td, J=10.1, 4.6 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H), 3.24-2.97 (m, 2H),1.50-1.29 (m, 9H), 1.32-1.17 (m, 12H).

(S)-2-(4-(3-((3-(tert-butoxy)-3-oxopropyl)amino)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylicacid (INT-33)

Prepared using General Procedure 19. Oven-dried lithium formate (136 mg,2.6 mmol), DIEA (700 μL, 3.9 mmol), and Ac₂O (370 μL, 3.9 mmol) weredissolved in anhydrous DMF (10 mL) in a flame-dried flask under N₂.After stirring for 30 min, the solution was degassed via N₂ bubbling. Ina separate flask, INT-28 (400 mg, 0.7 mmol, azeotropically dried fromTHF) was dissolved in DMF (10 mL) and degassed via N₂ bubbling. Into theINT-28 solution was added PdCl₂(dppf) (48 mg, 0.07 mmol) and theresulting solution was transferred via cannula into the lithium formatesolution. The flask was sealed and heated at 120° C. for 4 h in amicrowave reactor. The reaction mixture was diluted with EA (250 mL) andwashed with 10% citric acid (250 mL) and then washed with H₂O (250 mL)and purified by chromatography (EA/hexanes) to afford 400 mg (99%) of(S)-2-(4-(3-((3-(tert-butoxy)-3-oxopropyl)amino)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylicacid INT-33. LCMS-ESI (m/z) calculated for C₃₂H₃₈N₄O₆: 574.7; found575.3 [M+H]⁺, t_(R)=2.41 min. (Method 15).

Methyl 2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate

Prepared using General Procedure 7. To a stirring solution of methyl2-amino-2-(4-bromophenyl)acetate (421 mg, 1.5 mmol),4-(tert-butyl)benzoic acid (321 mg, 1.8 mmol), and DIEA (831 μl, 4.5mmol) in DMF (3 mL) cooled to 0° C. was slowly added a solution of HATU(380 mg, 1.65 mmol) in DMF (1.5 mL) in a drop-wise fashion. The reactionmixture was allowed to warm slowly and stirring continued for 4 h. Thereaction mixture was poured onto ice-water and the solid was filtered.The solid was dissolved in DCM (10 mL), dried over MgSO₄ and evaporatedto afford 532 mg (88%) of methyl2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate. LCMS-ESI (m/z)calculated for C₂₀H₂₂BrNO₃: 403.0; found 404.1 [M+H]⁺, t_(R)=3.61 min.(Method 16).

Methyl2-(4-(tert-butyl)benzamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(INT-34)

Prepared using General Procedure 10. A solution of methyl2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate (202 mg, 0.5 mmol),KOAc (147 mg, 1.5 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (165 mg,0.65 mmol) in DMSO (3 mL) was de-gassed. PdCl₂dppf (18 mg, 0.025 mmol)was added and the mixture was heated at 90° C. for 1.5 h. The crudereaction mixture was poured onto ice-water and the solid was filtered.The solid was dissolved in DCM (5 mL), dried over MgSO₄, evaporated andpurified by chromatography (EA/hexane) to provide 71 mg (31%) of methyl2-(4-(tert-butyl)benzamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateINT-34. LCMS-ESI (m/z) calculated for C₂₆H₃₄BNO₅: 451.3; found 452.2[M+H]⁺, t_(R)=3.83 min (Method 16).

(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2carboxamido)-propanoic acid

To a stirring solution of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 (15.7 g, 28.8 mmol) in DCM (30 mL) was treated with TFA (30.0 g,263.1 mmol). The reaction mixture was stirred at room temperature for 18hours to complete. The solvent was evaporated and then co-evaporatedwith toluene (3×20 mL) to remove trace TFA. The compound was dried undervacuum overnight to afford 13.7 g (97%) of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid as powder. LCMS-ESI (m/z) calculated for C₂₂H₂₂BrN₃O₃S: 487.1;found 488.1 [M+H]⁺, t_(R)=2.55 min. (Method 16). ¹H NMR (400 MHz, DMSO)δ 9.05 (d, J=5.0 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.1 Hz,2H), 7.62 (d, J=3.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.92 (d, J=3.8 Hz,2H), 4.64 (td, J=10.5, 4.5 Hz, 1H), 3.26 (dd, J=13.8, 4.4 Hz, 1H), 3.11(dd, J=13.7, 10.7 Hz, 1H), 1.32 (s, 9H).

Methyl(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate(INT-35)

To a stirring solution of methyl (S)-pyrrolidine-3-carboxylate (357.0mg, 2.16 mmol) in DMF (10 mL) were added DIEA (465.26 mg, 3.60 mmol) and(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid (700.0 mg, 1.44 mmol). The solution was cooled to 0° C. at ice bathand then HATU (677.55 mg, 2.88 mmol) in 2 mL DMF solution was slowlyadded. The reaction was stirred 1 hour at 0° C. and then warmed to RTwith stirring for 2 hours. The reaction solution was extracted with DCM(3×20 mL) and aqueous NaHCO₃ (3×10 mL). The combined organics were driedover MgSO₄ and evaporated. The final compound was purified by columnchromatography (40% DCM in hexane) to afford 501.0 mg (58%) of methyl(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylateINT-35 as a powder. LCMS-ESI (m/z calculated for C₂₈H₃₁BrN₄O₄S: 598.1;found 599.3 [M+H]⁺, t_(R)=3.553 min. (Method 16). ¹H NMR (400 MHz, DMSO)δ 9.05 (d, J=1.1 Hz, 2H), 8.77 (dd, J=11.5, 8.3 Hz, 1H), 8.25 (d, J=7.7Hz, 2H), 7.72 (d, J=3.5 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 6.92 (d, J=3.8Hz, 1H), 4.98-4.73 (m, 1H), 3.88 (dd, J=10.3, 8.0 Hz, 1H), 3.71 (dd,J=15.5, 7.5 Hz, 1H), 3.50 (ddd, J=18.3, 12.2, 5.4 Hz, 2H), 3.38 (dd,J=17.3, 7.6 Hz, 1H), 3.23 (ddd, J=28.0, 15.0, 8.7 Hz, 1H), 3.18-2.85 (m,3H), 2.17-1.96 (m, 2H), 1.87 (td, J=15.2, 7.4 Hz, 1H), 1.32 (s, 9H).

Tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninate

To a stirring solution of tert-butyl D-alaninate (5.60 g, 30.80 mmol) inDMF (50 mL) were added DIEA (8.29 g, 64.18 mmol) and(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid (12.5 g, 25.67 mmol). The solution was cooled to 0° C. at ice bathand then HATU (9.06 g, 38.50 mmol) in 15 mL DMF solution was slowlyadded. The reaction was stirred 1 hour at 0° C. and then warmed to RTwith stirring for 2 hours. The reaction solution was extracted with DCM(3×50 mL) and aqueous NaHCO₃ (3×30 mL). The combined organics were driedover MgSO₄ and evaporated. The final compound was purified by columnchromatography (40% DCM in hexane) to afford 14.7 g (94%) of tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninateassolid powder. LCMS-ESI (m/z) calculated for C₂₉H₃₅BRN₄O₄S: 614.2; found615.3 [M+H]⁺, t_(R)=3.914 min. (Method 16). ¹H NMR (400 MHz, CDCl₃) δ8.83 (d, J=3.6 Hz, 2H), 8.36 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H),7.34 (d, J=3.8 Hz, 1H), 6.81 (d, J=3.8 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H),6.34 (d, J=7.2 Hz, 1H), 4.88 (d, J=5.9 Hz, 1H), 4.41 (t, J=7.2 Hz, 1H),3.31 (dd, J=13.6, 5.8 Hz, 1H), 3.20 (dd, J=13.6, 7.8 Hz, 1H), 1.51-1.32(m, 18H), 1.27 (d, J=7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 172.02,171.31, 162.28, 162.13, 161.42, 158.55, 142.27, 136.34, 134.66, 130.20,128.82, 127.92, 123.07, 118.63, 80.90, 54.45, 48.86, 39.59, 39.38,32.39, 28.04, 17.68.

Tert-butyl((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)-pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(INT-36)

To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (224.6 mg,1.6 mmol), sodium carbonate decahydrate (96.0 mg, 1.6 mmol), tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninate(500.0 mg, 1.6 mmol), Pd(dppf)Cl₂ (58.5 mg, 0.08 mmol), THF (2.0 mL),CH₃CN (2.0 ml) and water (1.0 mL). The solution was degassed using N₂bubbling for 10 min. The reaction mixture was heated to 80° C. for 2hours. The reaction mixture was dried under reduced pressure to removethe solvent and diluted in DCM (20 mL). The mixture was extracted withDCM (3×20 mL) and aqueous NaHCO₃ (3×10 mL). The combined organics weredried over MgSO₄ and evaporated. The final compound was purified bycolumn chromatography (40% DCM in hexane) to afford 462.3 mg (91%) oftert-butyl((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninateINT-36 as a solid. LCMS-ESI (m/z) calculated for C₃₅H₄₀N₄O₅S: 628.3;found 629.3 [M+H]⁺, t_(R)=3.447 min. (Method 16). ¹H NMR (400 MHz, DMSO)δ 9.79 (s, 1H), 9.12 (s, 2H), 8.55 (t, J=16.2 Hz, 1H), 8.43 (d, J=7.2Hz, 1H), 8.30 (d, J=8.1 Hz, 2H), 7.69 (t, J=7.5 Hz, 3H), 7.50 (dd,J=15.4, 8.3 Hz, 2H), 7.00-6.85 (m, 2H), 6.75 (t, J=9.9 Hz, 1H), 4.80(td, J=9.7, 4.7 Hz, 1H), 4.15 (p, J=7.2 Hz, 1H), 3.10 (ddd, J=39.3,19.4, 11.8 Hz, 2H), 1.40 (d, J=6.6 Hz, 9H), 1.31 (s, 9H), 1.23 (t,J=11.1 Hz, 3H).

Methyl(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate(INT-37)

To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (60.7 mg, 0.44mmol), sodium carbonate decahydrate (26.4 mg, 0.44 mmol), methyl(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylateINT-35 (130.0 mg, 0.44 mmol), Pd(dppf)Cl₂ (16.09 mg, 0.022 mmol), THF(2.0 mL), CH₃CN (2.0 ml) and water (1.0 mL). The solution was degassedusing N₂ bubbling for 10 min. The reaction mixture was heated to 80° C.for 2 hours. The reaction mixture was dried under reduced pressure toremove the solvent and diluted in DCM (20 mL). The mixture was extractedwith DCM (3×10 mL) and aqueous NaHCO₃ (3×10 mL). The combined organicswere dried over MgSO₄ and evaporated. The final compound was purified bycolumn chromatography (50% DCM in hexane) to afford 102.0 mg (76%) ofmethyl(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylateINT-37 as a solid powder. LCMS-ESI (m/z) calculated for C₃₄H₃₆N₄O₅S:612.3; found 613.3 [M+H]⁺, t_(R)=3.138 min. (Method 16). ¹H NMR (400MHz, DMSO) δ 9.81 (s, 1H), 9.13 (d, J=1.5 Hz, 2H), 8.77 (dd, J=11.4, 8.1Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 7.73 (d, J=3.8 Hz, 1H), 7.69 (d, J=8.4Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 6.99-6.84 (m, 3H), 4.88 (s, 1H), 3.72(d, J=8.9 Hz, 1H), 3.62 (s, 1H), 3.59 (d, J=6.4 Hz, 1H), 3.50 (ddd,J=18.7, 12.0, 5.8 Hz, 1H), 3.36 (d, J=7.5 Hz, 1H), 3.27-3.16 (m, 1H),3.18-2.97 (m, 3H), 2.15-1.95 (m, 2H), 1.88 (dd, J=12.5, 7.5 Hz, 1H),1.32 (s, 9H).

Tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate(INT-38)

To a stirring solution of tert-butyl azetidine-3-carboxylate (64.55 mg,0.41 mmol) in DMF (1 mL) were added DIEA (169.6 mg, 1.31 mmol), and(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid (100.0 mg, 0.21 mmol). The solution was cooled to 0° C. at ice bathand then HATU (74.11 mg, 1.31 mmol) in 1 mL DMF solution was slowlyadded. The reaction was stirred 1 hour at 0° C. and then warmed to RTwith stirring for 2 hours. The reaction solution was extracted with DCM(3×10 mL) and aqueous NaHCO₃ (3×10 mL). The combined organics were driedover MgSO₄ and evaporated to afford 117.6 mg (85%) of tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylateINT-38 as a solid powder without further purification for next step.LCMS-ESI (m/z) calculated for C₃₀H₃₅BrN₄O₄S: 626.2; found 627.2 [M+H]⁺,t_(R)=3.884 min. (Method 16).

Methyl(S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate

Prepared using General Procedure 7. To a stirring solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid INT-22 (2082 mg, 2.75 mmol), methyl (S)-pyrrolidine-3-carboxylateHCl (545 mg, 3.30 mmol), and DIEA (1523 μl, 8.25 mmol) in DMF (6 mL)cooled to 0° C. was slowly added a solution of HATU (1254 mg, 3.30 mmol)in DMF (5 mL) in a drop-wise fashion The reaction mixture was allowed towarm slowly and stirring continued for 4 h. The reaction mixture waspoured onto ice-water and the solid was filtered. The solid wasdissolved in EA (50 mL), dried over MgSO₄, evaporated and purified bychromatography (EA/hexane) to provide 932 mg (52%) of methyl(S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate.LCMS-ESI (m/z) calculated for C₄₀H₄₆N₄O₆: 678.3; found 679.3 [M+H]⁺,t_(R)=4.50 min (Method 16).

Methyl(S)-1-((S)-2-amino-3-(4-(5-(4-(heptynyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate (INT-39)

Prepared using General Procedure 18: To a stirred solution of methyl(S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate(962 mg, 1.42 mmol) in MeOH (10 mL) was added palladium on carbon (10 wt%, 150 mg). The reaction mixture was flushed with hydrogen and stirredunder hydrogen at room temperature for 1.5 h. The reaction mixture wasfiltered through Celite and concentrated to give 752 mg (97%) of methyl(S)-1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate INT-39. LCMS-ESI (m/z) calculated forC₃₂H₄₀N₄O₄: 544.3; found 545.3 [M+H]⁺, t_(R)=3.61 min (Method 16).

(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid

Prepared using General Procedure 8: To a stirred solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate(1.08 g, 2.11 mmol) INT-7 in DCM (10 mL) was added TFA (5 mL). After 16h the mixture was diluted with toluene (10 mL) and evaporated. Furthertoluene (2×10 mL) was evaporated from the residue to afford 962 mg(100%) of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid as an off-white solid. LCMS-ESI (m/z) calculated for C₂₁H₁₈BrN₃O₄:455.1; found 456.0 [M+H]⁺, t_(R)=5.81 min (Method 10).

Tert-butyl((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(INT-42)

Prepared using General Procedure 7: To a stirred solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid (962 mg, 2.11 mmol) and (R)-tert-butyl 2-aminopropanoatehydrochloride (383 mg, 2.11 mmol) in DMF (20 mL) was added DIEA (1.2 mL,6.32 mmol). The mixture was cooled to 0° C. and HATU (802 mg, 2.11 mmol)was added portionwise. The cooling bath was removed and the mixture wasallowed to warm to room temperature. After 1 h the mixture was pouredonto citric acid (100 mL of a 0.1 M aqueous solution) and iso-hexanes(20 mL) and the resulting precipitate collected by filtration, washingsuccessively with water (2×10 mL), ACN (3 mL) and iso-hexanes (2×5 mL)to afford 1.1 g (89%) of tert-butyl((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl)-D-alaninateINT-42 as a white solid. LCMS-ESI (m/z) calculated for C₂₈H₃₁BrN₄O₅:582.2; found 605.2 [M+Na]⁺, t_(R)=7.94 min (Method 10).

2-amino-2-(2, 5-dimethyloxazol-4-yl)acetic acid hydrochloride

To a stirred solution of 2,5-dimethyloxazole-4-carbaldehyde (272 mg,2.17 mmol) and ammonium carbonate (564 mg, 5.87 mmol) in EtOH (6 mL) andwater (2 mL) at 50° C. was added dropwise over 20 minutes a solution ofpotassium cyanide (177 mg, 2.72 mmol) in water (3.8 mL). The solutionwas stirred at 60° C. for 16 h. The EtOH was distilled off at 80° C. andHCl added (0.2 mL of a 37% aqueous solution). The mixture was allowed tocool to room temperature and the precipitate collected by filtration,washing successively with water (5 mL) and iso-hexanes (2×5 mL). Thiswas dissolved in MeOH (14 mL) with stirring and treated with potassiumhydroxide (5.2 mL of a 2.5 M aqueous solution, 13.1 mmol) and thesolution stirred at 60° C. for 100 h. The mixture was allowed to cooland acidified with HCl. Solvents were evaporated and the residue treatedwith MeOH (10 mL). The mixture was filtered and the filtrate evaporatedto afford 205 mg (55%) of 2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acidhydrochloride as an orange oil. LCMS-ESI (m/z) calculated for C₇H₁₀N₂O₃:170.1; found 171.1 [M+H]⁺, t_(R)=0.23 min (Method 11). ¹H NMR (400 MHz,DMSO) δ 8.71 (br s, 3H), 5.13 (s, 1H), 2.38 (s, 3H), 2.34 (s, 3H).

Methyl 2-amino-2-(2,5-dimethyloxazol-4-yl)acetate hydrochloride (INT-43)

Prepared using General Procedure 22: To a stirred solution of2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acid hydrochloride (150 mg,0.726 mmol) in MeOH (5 mL) was added HCl (1.2 mL of a 37% aqueoussolution, 14.5 mmol) and the mixture heated under reflux for 4 h. Themixture was allowed to cool and solvents evaporated. The residue wastreated with MeOH (12 mL) and filtered. The filtrate was evaporated toafford 135 mg (84%) of methyl 2-amino-2-(2,5-dimethyloxazol-4-yl)acetatehydrochloride INT-43. LCMS-ESI (m/z) calculated for C₈H₁₂N₂O₃: 184.1;found 185.1 [M+H]⁺, t_(R)=0.23 min (Method 11). ¹H NMR (400 MHz, DMSO) δ8.94 (br s, 3H), 5.35 (s, 1H), 3.73 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H).

4-Benzyl 1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)phenyl)propanoyl)-L-aspartate(INT-47)

Prepared using General Procedure 7: To a stirred solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 192 (600 mg, 1.00 mmol), L-aspartic acid β-benzyl esterα-tert-butyl ester hydrochloride (398.4 mg, 1.20 mmol) in DMF (6 mL) wasadded DIEA (554 μl, 3.00 mmol). The mixture was cooled to 0° C. and HATU(418 mg, 1.10 mmol) in DMF (4 mL) was added over 5 mins. The mixture wasstirred at 0° C. for 0.5 h. The reaction mixture was added to water (250mL) and the precipitate was filtered. The precipitate was dissolved inDCM (20 mL), dried over MgSO₄, and concentrated. The crude product waspurified by chromatography 0-100% EA in hexane to afford 789 mg (92%) of4-benzyl 1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartateINT-47 as a white solid. LCMS-ESI (m/z) calculated for C₅₀H₆₀N₄O₇S:860.4; found 861.4 [M+H]⁺, t_(R)=6.028 min (Method 16).

(S)-4-(tert-butoxy)-3-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoicacid (INT-44)

Prepared using General Procedures 18: To 4-benzyl 1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartateINT-47 (345 mg, 0.4 mmol) in THF (5 mL) was added 10% Pd/C (60 mg). Thereaction vessel was flushed with hydrogen gas and the reaction wasstirred vigorously under hydrogen overnight at room temperature. Thereaction mixture was filtered to remove the catalyst, the solvent wasremoved, and the crude product was purified by chromatography 0-100% EAin hexane to afford 228 mg (66%) of(S)-4-(tert-butoxy)-3-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoicacid INT-44 as a white solid. LCMS-ESI (m/z) calculated for C₄₃H₅₄N₄O₇S:770.4; found 771.3 [M+H]⁺, t_(R)=4.21 min (Method 16).

Tert-butyl((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate(INT-45)

To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (317.23 mg,2.30 mmol), sodium carbonate decahydrate (138.0 mg, 2.3 mmol),tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoyl)-D-alaninateINT-32 (700.0 mg, 1.15 mmol), Pd(dppf)Cl₂ (87.8 mg, 0.12 mmol), THF (10mL), CH₃CN (10 ml) and water (5 mL). The solution was degassed using N₂bubbling for 10 min. The reaction mixture was heated to 80° C. for 2hours. The mixture was extracted with DCM (3×20 mL) and aqueous NaHCO₃(3×10 mL). The combined organics were dried over MgSO₄ and evaporated.The final compound was purified by column chromatography (40% DCM inhexane) to afford 595.0 mg (83%) of tert-butyl((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninateINT-45 as solid. LCMS-ESI (m/z) calculated for C₃₇H₄₂N₄O₅: 622.3; found623.3 [M+H]⁺, t_(R)=3.635 min. (Method 16). ¹H NMR (400 MHz, DMSO) δ9.79 (s, 1H), 9.11 (s, 2H), 8.50 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz,1H), 8.30 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.6 Hz,2H), 7.51 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.6 Hz,2H), 4.85 (td, J=9.9, 4.6 Hz, 1H), 4.17 (p, J=7.1 Hz, 1H), 3.24-3.00 (m,2H), 1.46-1.34 (m, 9H), 1.32-1.19 (m, 12H).

Tert-butylN²-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methyl-D-asparaginate

Prepared using General Procedures 7: To(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoicacid (205.7 mg, 0.5 mmol) in DMF (5 mL) at 0° C. was added HATU (380 mg,1.0 mmol). After stirring for 3 min, DIEA (277 μL, 1.5 mmol) andmethylamine (40 wt % in water, 116 μL, 1.5 mmol) were added. Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was added to water (75 mL) and the precipitate was filtered anddried to give 201 mg (95%) of tert-butylN²-(((9H-fluoren-9-yl)methoxy)carbonyl)-N⁴-methyl-D-asparaginate as acolorless semi-solid. LCMS-ESI (m/z) calculated for C₂₄H₂₈N₂O₅: 424.2;found 425.2 [M+H]⁺, t_(R)=3.22 min (Method 16).

Tert-butyl N⁴-methyl-D-asparaginate (INT-46)

To tert-butylN²-(((9H-fluoren-9-yl)methoxy)carbonyl)-N⁴-methyl-D-asparaginate (200mg, 0.47 mmol) in DCM (0.93 mL) was added piperidine (233 μL, 2.35mmol). The reaction mixture was stirred at room temperature for 1 h. Allsolvent was removed to give 215 mg of tert-butylN⁴-methyl-D-asparaginate as a mixture with1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used withoutpurification in the next reaction. LCMS-ESI (m/z) calculated forC₉H₁₈N₂O₃: 202.1; found 203.1 [M+H]⁺, t_(R)=0.534 min (Method 16).

Tert-butyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(INT-48)

Prepared using General Procedure 10. Into a solution of INT-38 (60 mg,0.1 mmol) in dioxane (2 mL) and H₂O (1 mL) were added sodium carbonate,decahydrate (60 mg, 0.2 mmol), 4-hydroxyphenylboronic acid (17 mg, 0.1mmol) and PdCl₂(dppf) (7 mg, 0.01 mmol). The mixture was heated at 80°C. for 2.5 h then cooled to room temp, diluted with H₂O (100 mL) andextracted into EA (2×100 mL). The resulting organic layers werecombined, dried (Na₂SO₄) and concentrated to yield 75 mg (117%) of crudetert-butyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(INT-48) which was used without further purification. LCMS-ESI (m/z)calculated for C₃₆H₄₀N₄O₅S: 640.8; found 341.3 [M+H]⁺, t_(R)=3.42 min.(Method 15).

Compound 492 was prepared from(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid INT-22 and (S)-methyl2-amino-6-((tert-butoxycarbonyl)amino)hexanoate hydrochloride usingGeneral Procedures 7, 18, 7, 4 and 8 sequentially.

Compounds 493, 494 and 500 were prepared from(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl) phenyl)propanoyl)pyrrolidine-2-carboxylic acid Compound328 using General Procedures 7 and 4 sequentially.

Compounds 495 and 496 were preparedfrom(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl) phenyl)propanoyl)pyrrolidine-2-carboxylic acid Compound328 using General Procedure 7.

Compound 497 was preparedfrom(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl) phenyl)propanoyl)-pyrrolidine-2-carboxylic acid Compound328 using General Procedures 7 and 8 sequentially.

Compounds 498 and 499 were prepared from(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid INT-22 using General Procedures 7, 18, 7 and 8 sequentially.

Compounds 501, 592-602, 604, 607-621, 625-629, 631, 633, 634, 636-641,644, 655, 668 and 669 were prepared from Compound 192 using GeneralProcedures 7 then 4.

Compound 502 was prepared from INT-30 using General Procedure 8.

Compounds 503-507, 579, and 580 were prepared from Compound 502 usingGeneral Procedures 7 then 18.

Compounds 508-511 were prepared from INT-31 using General Procedures 7then 8.

Compounds 512-523 were prepared from INT-44 using General Procedures 7then 8.

Compound 524 was prepared from INT-47 using General Procedure 8.

Compounds 525-533 were prepared from Compound 524 using GeneralProcedures 7 then 18.

Compound 534 was prepared from Compound 524 using General Procedures 7,18, then 8.

Compound 535 was prepared from Compound 192 using General Procedures 3then 8.

Compound 536 was prepared from(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 and 2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acidhydrochloride INT-43 using General Procedures 7 and 4 sequentially.

Compounds 537 and 554 were prepared from Compound 85 using GeneralProcedures 7 then 8.

Compounds 538-553, 555-578, 583-588, 622-624, 632 and 660-662 wereprepared from Compound 85 using General Procedures 7 then 4.

Compound 581 was prepared from Compound 85 using General Procedures 7, 4then 18.

Compound 582 was prepared from Compound 85 using General Procedures 7, 8then 4.

Tert-butyl(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate

Prepared using General Procedure 7. To a stirring solution of(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoicacid (308 mg, 0.75 mmol), methylamine (40 wt % in water, 174 μL, 2.25mmol), and DIEA (415 μl, 2.25 mmol) in DMF (7.5 mL) cooled to 0° C. wasadded HATU (569 mg, 1.5 mmol). The reaction mixture was allowed to warmslowly and stirring continued for 18 h. The reaction mixture was pouredonto ice-water and the solid was filtered. The solid was dissolved inDCM (10 mL), dried over MgSO₄ and evaporated. The crude product waspurified by column chromatography to afford 226 mg (71%) of tert-butyl(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate.LCMS-ESI (m/z) calculated for C₂₄H₂₈N₂O₅: 424.2; found 447.1 [M+Na]⁺,t_(R)=3.12 min. (Method 16).

Tert-butyl (R)-3-amino-4-(methylamino)-4-oxobutanoate

To a stirring solution of tert-butyl(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate(226 mg, 0.53 mmol), in DCM (1.05 mL) was added piperidine (263 μL, 2.7mmol). The reaction mixture was stirred for 1 h at room temperature. Thesolvent was evaporated to afford 250 mg (100%) of tert-butyl(R)-3-amino-4-(methylamino)-4-oxobutanoate as a mixture with1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used withoutpurification in the next reaction. LCMS-ESI (m/z) calculated forC₉H₁₈N₂O₃: 202.1; found 225.1 [M+Na]⁺, t_(R)=0.50 min. (Method 15).

Compound 589 was prepared from Compound 85 and tert-butyl(R)-3-amino-4-(methylamino)-4-oxobutanoate using General Procedures 7then 8.

Tert-butyl(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedure 7: A stirred solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid INT-22 (1 g, 1.76 mmol), tert-butylazetidine-3-carboxylate (0.554 g, 1.76 mmol) and DIEA (1.30 mL, 7.05mmol) in DMF (20 mL) at 0° C. was treated with HATU (0.703 g, 1.85mmol), added portionwise. After 10 min, the cooling bath was removed.After a further 1 h the mixture was poured onto 0.2 M HCl (100 mL) andextracted with EA (3×30 mL). The combined organic extracts were washedwith brine (20 mL), dried over MgS₄ and evaporated. Columnchromatography (EA/DCM/iso-hexanes) gave 708 mg (58%) of tert-butyl(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylateas an off-white solid. LCMS-ESI (m/z) calculated for C₄₂H₅₀N₄)₆: 706.4;found 707.1 [M+H]⁺, t_(R)=3.60 min (Method 6).

Tert-butyl(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedures 18 and 7: To a stirred solution of(S)-tert-butyl1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(708 mg, 1.00 mmol) and triethylsilane (352 μL, 2.20 mmol) in DCM (10mL) was added a solution of diacetoxypalladium (22.5 mg, 0.100 mmol) andtriethylamine (43 μL, 0.30 mmol) in DCM (2 mL). After 16 h, the mixturewas filtered through Celite and solvents evaporated. The residue wastaken up in DMF (6 mL) and the resulting solution added to a stirredsolution of active ester prepared by the action of HATU (399 mg, 1.05mmol) and DIEA (0.55 mL, 3.00 mmol) on 4-(tert-butyl)benzoic acid (196mg, 1.10 mmol) in DMF (5 mL) over 10 min. After 1 h, the mixture waspoured onto 0.5 M HCl (100 mL) and extracted with EA (3×50 mL). Thecombined organic extracts were washed with brine (20 mL), dried overMgSO₄ and evaporated. Column chromatography (EA/DCM/iso-hexanes) gave583 mg (80%) of tert-butyl(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.LCMS-ESI (m/z) calculated for C₄₅H₅₆N₄O₅: 732.4; no m/z observed,t_(R)=3.99 min (Method 11).

(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 590)

Prepared using General Procedure 8: To a stirred solution of(S)-tert-butyl1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(580 mg, 0.791 mmol) in DCM (6 mL) was added TFA (2 mL). After 3 h, themixture was diluted with toluene (20 mL) and the solvents evaporated.Column chromatography (acetic acid/EA/DCM/iso-hexanes) gave moderatelypure product. This was further purified by re-slurry from DCM/ACN theniso-propyl acetate. The resulting solid was again purified by columnchromatography (acetic acid/EA/DCM/iso-hexanes) then reslurried fromdiethyl ether to afford 212 mg (40%) of(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-propanoyl)azetidine-3-carboxylicacid Compound 590. LCMS-ESI (m/z) calculated for C₄₁H₄₈N₄O₅; 676.4; nom/z observed, t_(R)=10.23 min (Method 10). The chiral purity was >95%e.e (chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.16 (d,J=1.5 Hz, 2H), 8.75 (dd, J=8.1, 3.7 Hz, 1H), 8.36-8.31 (m, 2H),7.85-7.75 (m, 4H), 7.49-7.46 (m, 4H), 7.11-7.05 (m, 2H), 4.74-4.68 (m,1H), 4.45 (t, J=8 Hz, 0.5H), 4.33-4.30 (m, 0.5H), 4.24-4.16 (m, 1H),4.06-4.00 (m, 3H), 3.47-3.40 (m, 1H), 3.90 (ddd, J=13.5, 9.7, 6.0 Hz,1H), 3.18-3.05 (m, 2H), 1.77-1.70 (m, 2H), 1.46-1.24 (m, 17H), 0.89-0.86(m, 3H).

Compound 591 was prepared from Compound 85 and INT-46 using GeneralProcedures 7 then 8.

Compounds 603, 605, 645-648, 652, 653, 656-659 and 664 were preparedfrom Compound 192 using General Procedures 7 then 8.

Compound 606 was prepared from Compound 192 using General Procedures 7,4 then 8.

Compound 630 was prepared from Compound 192 and tert-butyl(R)-3-amino-4-(methylamino)-4-oxobutanoate using General Procedures 7then 8.

(S)-methyl1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedure 7: To a stirred solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-propanoicacid INT-22 (2.2 g, 3.88 mmol) and methyl azetidine-3-carboxylate, HCl(0.705 g, 4.65 mmol) in DMF (25 mL) was added DIEA (2.7 mL, 15.5 mmol)and the mixture cooled to 0° C. HATU (1.621 g, 4.26 mmol) was addedportion-wise over 10 minutes. After 3 h further methylazetidine-3-carboxylate, HCl (0.223 g, 1.938 mmol) and HATU (0.456 g,1.938 mmol) were added. The mixture was allowed to stir at roomtemperature for 100 h. The mixture was treated with citric acid (50 mLof a 0.1 M aqueous solution) and water (20 mL) and extracted with EA(2×100 mL). The combined organic extracts were washed with brine (80mL), dried over MgSO₄ and solvents evaporated. Column chromatography(EA/iso-hexanes) gave 1.45 g (56%) of(S)-methyl1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylateas a colourless glass. LCMS-ESI (m/z) calculated for C₃₉H₄₄N₄O₆: 664.3;found 665.3 [M+H]⁺, t_(R)=3.37 min (Method 6).

(S)-methyl1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-azetidine-3-carboxylate

Prepared using General Procedure 18: A solution of (S)-methyl1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-propanoyl)azetidine-3-carboxylate(1.2 g, 1.81 mmol) in MeOH (150 mL) was passed over a 10% Pd/C CatCart(55×4 mm) at 65° C. in a Thales Nanotechnology H-Cube reactor at 2.1mL/min. The solvent was evaporated and the residue purified by columnchromatography (Ammonia/MeOH/DCM) to afford 604 mg (63%) of (S)-methyl1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.LCMS-ESI (m/z) calculated for C₃₁H₃₈N₄O₄: 530.3; found 531.0 [M+H]⁺,t_(R)=1.60 min (Method 6).

Methyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

To a stirred solution of (S)-methyl1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(360 mg, 0.678 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (125mg, 0.678 mmol) in DMF (6 mL, 77 mmol) was added DIEA (0.47 mL, 2.71mmol) and the mixture cooled to 0° C. HATU (284 mg, 0.746 mmol) wasadded portion-wise and the reaction stirred at room temperature for 1 h.The mixture was poured onto citric acid (70 mL of a 10% w/w aqueoussolution) and extracted with EA (2×100 mL). The combined organicextracts were washed with brine (50 mL), dried over MgSO₄ and solventsevaporated. Column chromatography (EA/iso-hexanes) gave 389 mg (82%) of(S)-methyl1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylateas a pale yellow solid. LCMS-ESI (m/z) calculated for C₄₀H₄₈N₄O₅S:696.3; found 697.0 [M+H]⁺, t_(R)=3.60 min (Method 6).

(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 635)

To a stirred solution of (S)-methyl1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(341 mg, 0.489 mmol) in THF (10 mL) was added sulfuric acid (3 mL of a 5M aqueous solution, 15 mmol). After 24 h, the mixture was diluted withwater (100 mL) and extracted with EA (2×100 mL). The combined organicextracts were washed with brine (50 mL), dried over MgSO₄ and solventsevaporated. Column chromatography (AcOH/EA/DCM/iso-hexanes) gave 233 mg(70%) of(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid Compound 635 as a white solid. LCMS-ESI (m/z) calculated forC₃₉H₄₆N₄O₅S: 682.3; no m/z observed, t_(R)=10.17 min (Method 10). Thechiral purity was >98% e.e. (Chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ12.75 (s, 1H), 9.17 (d, J=1.8 Hz, 2H), 8.77 (app dd, J=8.3, 2.7 Hz, 1H),8.32 (dd, J=8.2, 4.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.70 (d, J=3.9 Hz,1H), 7.47-7.52 (m, 2H), 7.11-7.07 (m, 2H), 6.93 (app dd, J=3.9, 1.4 Hz,1H), 4.70-4.63 (m, 1H), 4.43 (t, J=9.0 Hz, 0.5H), 4.30 (dd, J=8.7, 6.0Hz, 0.5H), 4.21 (t, J=8.9 Hz, 0.5H), 4.15 (dd, J=8.5, 6.3 Hz, 0.5H),4.08-3.99 (m, 3H), 3.47-3.40 (m, 1H), 3.93-3.87 (m, 1H), 3.15-3.01 (m,2H), 1.77-1.70 (m, 2H), 1.49-1.16 (m, 17H), 0.88 (t, J=6.8 Hz, 3H).

Compound 642 was prepared from(2S,3R)-2-amino-3-hydroxy-3-phenylpropanoic acid and(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid Compound 192 using General Procedures 26, 7 and 8 sequentially.

Compounds 650 and 654 were prepared from Compound 635 using GeneralProcedure 7.

Compound 649 was prepared from Compound 654 using General Procedure 4.

Threo-methyl 2-amino-3-hydroxy-3-phenylpropanoate HCl

Prepared using General Procedure 22: To a stirred solution ofthreo-2-amino-3-hydroxy-3-phenylpropanoic acid (7 g, 38.6 mmol) in MeOH(20 mL) was added chlorotrimethylsilane (19.8 mL, 155 mmol). The mixturewas heated under reflux for 16 h then solvents evaporated to afford 8.95g (100%) of threo-methyl 2-amino-3-hydroxy-3-phenylpropanoate HCl.LCMS-ESI (m/z) calculated for C₁₀H₁₃NO₃; 195.1; found 196.0 [M+H]⁺,t_(R)=0.18 min (Method 10). ¹H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 3H),7.42-7.31 (m, 5H), 5.03 (d, J=5.4 Hz, 1H), 4.18 (app t, J=5.4 Hz, 1H),3.63 (s, 3H).

Threo-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate

Prepared using General Procedure 23: To a stirred mixture ofthreo-methyl 2-amino-3-hydroxy-3-phenylpropanoate, HCl (1.1 g, 4.75mmol), MeOH (10 mL) and NaHCO₃ (8.44 mL of a 0.9 M aqueous solution,7.60 mmol) was added di-tert-butyl dicarbonate (1.451 g, 6.65 mmol).After 3 h, the bulk of the MeOH was evaporated under reduced pressureand the aqueous extracted with diethyl ether (2×40 mL). The combinedorganic extracts were dried over MgSO₄ and solvents evaporated. Theresidue was re-slurried from iso-hexanes and the solid collected byfiltration to afford 1.1 g (78%) of threo-methyl2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate. LCMS-ESI(m/z) calculated for C₁₅H₂₁NO₅: 295.1; found 318.0 [M+Na]⁺, t_(R)=4.45min (Method 10).

Methyl 2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropanoate

Prepared using General Procedure 24: To a stirred solution of oxalylchloride (0.47 ml, 5.42 mmol) in DCM (50 mL) at −78° C. was added DMSO(0.77 mL, 10.8 mmol) and the reaction stirred for 10 mins. This was thentreated with a pre-cooled solution of threo-methyl2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate (1 g, 3.39mmol) in DCM (20 mL). After 2 h, DIEA (2.96 mL, 16.93 mmol) was addedand the mixture allowed to warm to 0° C. After 1 h, the mixture waswashed with NH₄Cl (2×20 mL of a saturated aqueous solution) and theorganics dried over MgSO₄ and solvents evaporated to afford 964 mg (97%)of methyl 2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropanoate.LCMS-ESI (m/z) calculated for C₁₅H₁₉NO₅: 293.1; found 316.0 [M+Na]⁺,t_(R)=2.15 min (Method 11).

Erythro-methyl2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate

Prepared using General Procedure 25: To a stirred solution of methyl2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropanoate (0.5 g, 1.705mmol) in MeOH (10 mL) at −78° C. was added sodium borohydride (0.045 g,1.193 mmol). After 0.5 h, the reaction was quenched with NH₄Cl (8 mL ofa saturated aqueous solution) and the MeOH evaporated under reducepressure. The mixture was extracted with DCM (2×30 mL) and the combinedorganic extracts dried over MgSO₄ and solvents evaporated. The residuewas purified by column chromatography (EA/iso-hexanes) to afford 312 mg(62%) of erythro-methyl2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate. LCMS-ESI(m/z) calculated for C₁₅H₂₁NO₅: 295.1; found 318.0 [M+Na]⁺, t_(R)=1.84min (Method 11).

Erythro-methyl 2-amino-3-hydroxy-3-phenylpropanoate

Prepared using General Procedure 8: To a stirred solution oferythro-methyl2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate (0.3 g, 1.02mmol) in DCM (15 mL) was added TFA (1.57 mL, 20.32 mmol). After 3 h,solvents were evaporated and the residue purified bystrong-cation-exchange ion exchange chromatography to afford 195 mg(98%) of erythro-methyl 2-amino-3-hydroxy-3-phenylpropanoate as a whitesolid. LCMS-ESI (m/z) calculated for C₁₀H₁₃NO₃: 195.2; found 196.0[M+Na]⁺, t_(R)=0.19 min (Method 11).

Compound 651 was prepared fromerythro-2-amino-3-hydroxy-3-phenylpropanoic acid and(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid Compound 192 using General Procedures 7 and 4 sequentially.

Compound 663 was prepared from Compound 192 and INT-46 using GeneralProcedures 7 then 8.

Compound 665 was prepared fromerythro-2-amino-3-hydroxy-3-phenylpropanoic acid and(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid Compound 192 using General Procedures 7 and 4 sequentially,followed by chiral preparative HPLC.

Methyl (2,3-erythro)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoate

Prepared using General Procedure 7: To a stirred solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-propanoicacid Compound 192 (578 mg, 0.963 mmol) and erythro-methyl2-amino-3-hydroxy-3-phenylpropanoate (188 mg, 0.963 mmol) in DMF (8 mL)was added DIEA (503 μL, 2.89 mmol). The mixture was cooled to 0° C. andtreated with HATU (384 mg, 1.01 mmol), added portionwise. The coolingbath was removed and the reaction allowed to stir for 2 h. The mixturewas treated with citric acid (100 mL of a 10% w/v aqueous solution) andextracted with EA (3×20 mL). The combined organic extracts were driedover MgSO₄ and solvents evaporated. Column chromatography(EA/iso-hexanes) gave 654 mg (87%) ofmethyl(2,3-erythro)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoateas a white solid. LCMS-ESI (m/z) calculated for C₄₅H₅₂N₄O₆S: 776.4; nom/z observed, t_(R)=3.24 min (Method 11).

(2R,3R)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoicacid (Compound 666)

Prepared using General Procedure 4: To a stirred solution ofmethyl(2,3-erythro)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)-phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoate(327 mg, 0.421 mmol) in THF (5 mL) was added LiOH (231 μL of a 2 Maqueous solution, 0.463 mmol). After 30 minutes the mixture was pouredinto citric acid (25 mL of a 10% w/v aqueous solution) and extractedwith DCM (3×30 mL). The combined organic extracts were dried over MgSO₄and solvents evaporated. The residue was purified by columnchromatography (AcOH/MeOH/DCM) then preparative chiral HPLC to afford 15mg (5%) of(2R,3R)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)-phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoicacid Compound 666. LCMS-ESI (m/z) calculated for C₄₄H₅₀N₄O₆S: 762.4; nom/z observed, t_(R)=10.68 min (Method 10). The chiral purity was >70%d.e. (Chiral Method 2). ¹H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.15(s, 2H), 8.51 (d, J=9.3 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.27-8.23 (m,2H), 7.80-7.77 (m, 2H), 7.61 (d, J=3.9 Hz, 1H), 7.42-7.37 (m, 4H),7.27-7.20 (m, 3H), 7.10-7.08 (m, 2H), 6.89 (d, J=3.9 Hz, 1H), 5.81 (s,1H), 4.80 (d, J=8.8 Hz, 1H), 4.68-4.62 (m, 1H), 4.55 (t, J=9.0 Hz, 1H),4.04 (t, J=6.5 Hz, 2H), 2.59-2.52 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.29(m, 17H), 0.94-0.83 (m, 3H).

(2R,3S)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoicacid (Compound 667)

Prepared using General Procedures 7 and 4: To a stirred solution ofthreo-methyl 2-amino-3-hydroxy-3-phenylpropanoate (50 mg, 0.256 mmol)and(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 192 (140 mg, 0.233 mmol) in DMF (3 mL) was added DIEA (122μL, 0.699 mmol) and the mixture cooled to 0° C. HATU (97 mg, 0.256 mmol)was added portionwise and the mixture allowed to warm to roomtemperature over 2 h. The mixture was treated with citric acid (40 mL ofa 5% w/v aqueous solution) and the liquid decanted. The aqueous wasextracted with EA (50 mL) and this used to dissolve the solid residue.This solution was diluted with toluene (5 mL) and solvents evaporated.The residue was purified by column chromatography (ACN/DCM). Theintermediate ester thus obtained was dissolved in THF/MeOH (1:1, 3 mL)and allowed to stir with LiOH (0.23 mL of a 2 M aqueous solution, 0.46mmol). After 16 h, further LiOH (0.58 mL of a 2 M aqueous solution, 1.17mmol) was charged. After an additional 1 h, the mixture was treated withcitric acid (20 mL of a 10% w/v aqueous solution) and the precipitatecollected by filtration. Purification by preparative chiral HPLC gave 5mg (3%) of(2R,3S)-2((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)-phenyl)propanamido)-3-hydroxy-3-phenylpropanoicacid Compound 667. LCMS-ESI (m/z) calculated for C₄₄H₅₀N₄O₆S: 762.4; nom/z observed, t_(R)=10.63 min (Method 10). The chiral purity was <80%d.e. (chiral Method 2). ¹H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.08(s, 2H), 8.30 (dd, J=17.6, 9.1 Hz, 2H), 8.24-8.13 (m, 2H), 7.78-7.66 (m,2H), 7.53 (d, J=3.9 Hz, 1H), 7.32 (app ddd, J=16.7, 7.6, 1.8 Hz, 4H),7.25-7.08 (m, 3H), 7.08-6.90 (m, 2H), 6.83 (d, J=3.8 Hz, 1H), 5.81 (d,J=4.6 Hz, 1H), 5.17 (s, 1H), 4.72 (ddd, J=11.0, 9.0, 3.9 Hz, 1H), 4.50(dd, J=9.2, 2.8 Hz, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.78 (dd, J=13.8, 3.7Hz, 1H), 2.68-2.54 (m, 1H), 1.75-1.59 (m, 2H), 1.42-1.12 (m, 17H),0.89-0.75 (m, 3H).

Compound 670 was prepared from INT-34 and5-(4-(heptyloxy)phenyl)-2-iodopyrimidine using General Procedure 10.

Compound 671 was prepared from 2-chloroquinolin-6-ol and 1-bromoheptaneusing General Procedure 12, General Procedure 10 using INT-13, thenGeneral Procedure 8.

Compound 672 was prepared from 3-chloroisoquinolin-7-ol and1-bromoheptane using General Procedure 12, General Procedure 10 usingINT-13, and General Procedure 8.

Compound 673 was prepared from 2-chloroquinazolin-6-ol and1-bromoheptane using General Procedure 12, General Procedure 10 usingINT-13, then General Procedure 8.

Compound 674 and 693 were prepared from INT-28 using General Procedure11 then 8.

Compounds 675-691, 694, 695 and 696 were prepared from INT-28 usingGeneral Procedures 10 and 8.

Compounds 692, 744-748, 751-755, 758-760 were prepared from commercialnitriles using General Procedure 2, then General Procedure 5 usingINT-33 and General Procedure 8.

Compounds 697-705 were prepared by coupling commercial phenol boronicacids and INT-28 using General Procedure 10 followed by GeneralProcedures 12 and 8.

Compounds 706-716, and 803 were prepared from INT-29 using GeneralProcedures 12 and 8.

Compounds 717-742 and 800 were prepared from INT-32 using GeneralProcedures 10 then 8.

Compounds 743, 749, 750, 756 and 757 were prepared from INT-33 usingGeneral Procedure 5 and 8.

Compounds 761-769 were prepared from INT-35 using General Procedures 10then 4.

Compounds 770 and 771 were prepared from INT-36 using General Procedures12 then 8.

Compounds 772-774 were prepared from INT-37 using General Procedures 12then 4.

Compound 775 was prepared from INT-38 using General Procedures 10 then8.

Compound 776 was prepared from (3-methyl-4-hydroxyphenyl)boronic acidand INT-38 using General Procedure 10, then with 1-bromoheptane usingGeneral Procedure 12 then 8.

Compounds 777-789 were prepared from INT-38 using General Procedures 10then 8.

Compound 790 was prepared from (4-hydroxy-2-methylphenyl)boronic acidand (R)-tert-butyl2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanamido)propanoateINT-42 using General Procedures 10, 12, 18, 7 and 8 sequentially.

Compound 791 was prepared from 4-bromo-3,5-dimethylphenol and(R)-tert-butyl2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanamido)propanoateINT-42 using General Procedures 12, 27, 10, 18, 7 and 8 sequentially.

Compounds 792-794 were prepared from INT-45 using General Procedures 12then 8.

Compounds 795-797 and 799 were prepared from INT-48 using GeneralProcedures 12 then 8.

Tert-butyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl-)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedure 12: To a stirred solution of INT-48(300 mg, 0.479 mmol) in DMF (5 mL) was added Cs₂CO₃ (197 mg, 0.58 mmol)and 1-bromo-4-methylpentane (158 mg, 0.96 mmol). The reaction mixturewas stirred for 18 h at 65° C. then diluted with aq. NaHCO₃ (100 ml,saturated) and extracted with EA (2×100 mL). The combined organic layerswere dried (Na₂SO₄), concentrated, and purified by column chromatography(EA/hexane) to afford 188 mg (54%) of tert-butyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.LCMS-ESI (m/z) calculated for C₄₂H₅₂N₄O₅S: 724.96; found 725.3 [M+H]⁺,t_(R)=12.71 min (Method 16). ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J=7.5Hz, 2H), 8.45 (d, J=5.5 Hz, 2H), 7.55 (s, 2H), 7.49-7.31 (m, 3H), 7.05(d, J=6.6 Hz, 2H), 6.82 (s, 1H), 6.68 (d, J=28.8 Hz, 1H), 4.82 (s, 1H),4.30 (s, 0.5H), 4.07 (m, 5.5H), 3.56 (s, 0.5H), 3.31-3.09 (m, 2H), 2.91(s, 0.5H), 1.83 (s, 2H), 1.60 (d, J=25.3 Hz, 1H), 1.40 (s, 16H), 1.29(s, 4H), 0.95 (s, 6H).

(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (798)

Prepared using General Procedure 8: To a stirred solution of tert-butyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(188 mg, 0.26 mmol), in DCM (2 mL) was added TFA (2 mL). The mixture wasstirred for 4 h then concentrated. The resulting solid was dissolved inDCM (10 mL) and concentrated (5×) to remove excess TFA, affording 169 mg(98%) of1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid 798 as a yellow solid. LCMS-ESI (m/z) calculated for C₃₈H₄₄N₄O₅S:668.85; found 669.3 [M+H]⁺, t_(R)=9.121 min (Method 16). ¹H NMR (400MHz, CDCl₃) δ 9.17 (s, 2H), 8.12 (d, J=7.8 Hz, 2H), 7.58 (m, 3H), 7.45(m, 1H), 7.42 (m, 2H), 7.06 (m, 2H), 6.84 (m, 1H), 4.71 (d, J=7.7 Hz,1H), 4.33-4.14 (m, 2H), 4.08 (dd, J=19.8, 9.1 Hz, 2H), 4.03 (t, J=6.6Hz, 2H), 3.30 (dd, J=12.5, 4.2 Hz, 1H), 3.06 (t, J=11.9 Hz, 1H), 2.91(s, 1H), 1.91-1.76 (m, 2H), 1.64 (dt, J=13.0, 6.6 Hz, 1H), 1.43-1.33 (m,11H), 0.95 (d, J=6.6 Hz, 6H).

Compound 801 was prepared from Compound 2 using General Procedures 7then 8.

Compound 802 was prepared from Compound 83 using General Procedures 7then 8.

Compound 804 was prepared from Compound 267 using General Procedures 7and 8.

Compounds 806 and 807 were prepared from compound 671 using GeneralProcedures 7 then 8.

Compound 808 was prepared from compound 672 using General Procedures 7then 8.

Compound 809 and 810 were prepared from 673 using General Procedures 7then 8.

Compound 811 was prepared from (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-6 and 5-bromo-2-iodopyridine using General Procedures 10, 10, 8, 7,18, 7 and 8 sequentially.

Compound 812 was prepared from 2-bromo-5-iodo-3-methylpyridine and(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-6 using General Procedures 10, 10, 8, 7, 18, 7 and 8 sequentially.

Compounds 813-830 and 832-843 were prepared from INT-24 using GeneralProcedures 7 then 8.

Compounds 844 853 and 855-868 were prepared from INT-39 using GeneralProcedures 7 then 8.

Compounds 869 and 870 were prepared from Compound 90 using GeneralProcedures 7 then 8.

Compounds 871-879 were prepared from Compound 192 using GeneralProcedures 7 then 8.

Compounds 880-882 and 888 were prepared from Compound 192 using GeneralProcedures 7 then 4.

Compound 883 was prepared from Compound 192 and methyl (2S,3S)-2-amino-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoate usingGeneral Procedures 7, 4 then 8.

Compounds 884, 885 and 887 were prepared from Compound 349 using GeneralProcedure 7.

Compound 886 was prepared from Compound 192 using General Procedure 7.

Compound 889 was prepared from Compound 192 using General Procedures 7then 8.

Methyl 2-amino-3-methoxy-3-phenylpropanoate

To a stirring solution of threo-methyl2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate (148 mg, 0.5mmol) in DCM (5 mL) was added proton sponge (430 μL, 2.0 mmol), 4 Åmolecular sieves (520 mg) and trimethyloxonium tetrafluoroborate (260mg). The reaction mixture was stirred vigorously at room temperature for24 hours and the solids were removed by filtration. The filtrate waswashed with 10% aqueous copper sulfate (10 mL), saturated aqueousammonium chloride (10 mL), saturated aqueous sodium bicarbonate (10 mL),and brine (10 mL). The organic layer was dried over magnesium sulfateand concentrated. The crude compound was purified by columnchromatography (0-100% EA in hexanes) to afford 86 mg of methyl2-((tert-butoxycarbonyl)amino)-3-methoxy-3-phenylpropanoate which wasdissolved in DCM (1 mL) and treated with TFA (425 μL). After 1 hour, allsolvent was removed to give 96 mg (59%) of methyl2-amino-3-methoxy-3-phenylpropanoate. LCMS-ESI (m/z) calculated forC₁₁H₁₅NO₃: 209.1; found 210.1 [M+H]⁺, t_(R)=1.46 min (Method 16).

Compound 890 was prepared from methyl2-amino-3-methoxy-3-phenylpropanoate and Compound 192 using GeneralProcedures 7 then 4.

Compound 891 was prepared from 1-tert-butyl 3-methylpiperazine-1,3-dicarboxylate and Compound 192 using General Procedures7, 4 then 8.

Compound 892 was prepared from 1,3-pyrrolidinedicarboxylic acid,5-methyl-, 1-(1,1-dimethylethyl) ester using General Procedures 22 then8, and Compound 192 using General Procedures 7 then 4.

Compound 893 was prepared from Compound 85 and1,3-pyrrolidinedicarboxylic acid, 5-methyl-, 1-(1,1-dimethylethyl) esterusing General Procedures 22, 8, 7 then 4.

Compound 894 was prepared from 3-(aminomethyl)-1-methylpyrrolidin-3-oland Compound 192 using General Procedure 7.

Compound 895 was prepared from Compound 192 and (2R,3R)-methyl2-amino-3-hydroxybutanoate hydrochloride using General Procedures 7, 28and 29 sequentially.

Compounds 896-899 were prepared from 2-amino-3-phenylbutanoic acid usingGeneral Procedure 22, and INT-22 using General Procedures 7, 18, 7 and 4sequentially.

Compounds 900-908 and 911-918 were prepared from a suitableaminoalcohol, prepared using General Procedure 30, and Compound 192using General Procedures 7 and 8 sequentially.

Compound 909 was prepared from (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-phenylbutanoic acid using GeneralProcedure 22, and Compound 192 using General Procedures 7 and 4sequentially.

Compound 910 was prepared from(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-phenylbutanoic acid usingGeneral Procedure 22, and Compound 192 using General Procedures 7 and 4sequentially.

Compounds 919-922, 944 and 945 were prepared from INT-48 using GeneralProcedures 12 then 8.

Tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate

Prepared using General Procedure 7. To a stirring solution of tert-butyl2-amino-3-(tert-butoxy)-3-phenylpropanoate (198 mg, 0.7 mmol) in DMF (5mL) were added DIEA (267 μL, 1.54 mmol), and INT-17 (300 mg, 0.6 mmol).The solution was cooled to 0° C. at ice bath and then HATU (245 mg, 0.6mmol) was added. The reaction was stirred for 1 hour at 0° C. and thenwarmed to RT with stirring for 2 hours. The reaction solution wasdiluted with aqueous NaHCO₃ (50 mL) and extracted with EA (3×50 mL). Thecombined organics were dried over Na₂SO₄ and purified by chromatography(EA/Hexanes) to afford 308 mg (67%) of tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate.LCMS-ESI (m/z) calculated for C₃₉H₄₇BrN₄O₅S: 763.79; found 764.2 [M+H]⁺,t_(R)=4.64 min. (Method 15).

Compounds 925-934 and 943 were prepared from tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoateusing General Procedure 10 then 8.

Tert-butyl3-(tert-butoxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-3-phenylpropanoate(INT-51)

To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (63 mg, 0.5mmol), sodium carbonate decahydrate (217 mg, 0.8 mmol), tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate(290 mg, 0.4 mmol), Pd(dppf)Cl₂ (28 mg, 0.04 mmol), dioxane (10.0 mL),and water (2.0 mL). The reaction mixture was heated to 80° C. overnight.The reaction mixture was dried under reduced pressure to remove thesolvent and diluted in DCM (20 mL). The mixture was washed with aqueousNaHCO₃ (3×10 mL). The combined organics were dried over Na₂SO₄ andevaporated to afford 309 mg (106%) of crude tert-butyl3-(tert-butoxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-3-phenylpropanoateINT-51 which was used without further purification. LCMS-ESI (m/z)calculated for C₄₅H₅₂N₄O₆S: 776.9; found 721 [M−^(t)BuO]⁺, t_(R)=11.03min. (Method 14).

Compounds 923, 924 and 935-942 were prepared from INT-51 using GeneralProcedure 12 followed by General Procedure 8.

Compound 946 was prepared from 2-bromo-5-iodo-3-methylpyridine and4-(heptyloxy)phenyl boronic acid using General Procedure 10, and thenwith INT-6 using General Procedures 10, 18, 7 and 8 sequentially.

Compounds 947-960 were prepared from INT-49 using General Procedures 7then 4.

Compounds 961-978 were prepared from Compound 192 using GeneralProcedure 7.

Compounds 984-989, 991 and 1047 were prepared from Compound 192 usingGeneral Procedures 7 then 8.

Compounds 979-983 and 990 were prepared from Compound 24 using GeneralProcedures 7 then 8.

Compounds 992-1046 and 1050-1055 were prepared from tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninateusing General Procedures 10 then 8.

Compounds 1048 and 1049 were prepared from Compound 192 using GeneralProcedures 7 then 8.

Selected compounds and their corresponding analytical data are shown inTable 1, where the LCMS data was collected using the method indicated.

Lengthy table referenced here US20170313717A1-20171102-T00001 Pleaserefer to the end of the specification for access instructions.

Biological Assays Assay Procedures

GLP-1 PAM Shift cAMP Assay: Dose Response of Peptide Ligand in Presenceof Fixed Concentration of Compound

A GLP-1R expressing CRB-bla CHO-K1 cell line was purchased fromInvitrogen. Cells were seeded into 384-well white flat bottom plates at5000 cells/well/20 L growth media (DMEM-High glucose, 10% dialyzed FBS,0.1 mM NEAA, 25 mM Hepes, 100 U/mL penicillin/100 μg/mL streptomycin, 5μg/mL Blasticidin, 600 μg/mL Hygromycin) and incubated for 18 h at 37°C. in 5% CO₂. Growth medium was replaced with 12 μL assay buffer (HanksBalanced Salt solution, 10 mM Hepes, 0.1% BSA, pH 7.4). A 5× peptidedose response curve (12-point) was generated in assay buffer containing1.5 mM IBMX, 12.5% DMSO, and 50 μM compound. Peptide ligand wasGLP-1(9-36). The 5× peptide dose response plus compound mix was added (3μL) and cells were incubated for 30 min at 37° C. Direct detection ofcAMP was carried out using DiscoveRx HitHunter cAMP kit according tomanufacturer's instructions and luminescence was read using a SpectraMaxM5 plate reader. Luminescence was analyzed by non-linear regression todetermine the EC₅₀ and Emax. A GLP-1(7-36) dose response was included todetermine maximum efficacy.

EC₂₀ GLP-1(9-36) PAM cAMP assay: dose response of compound in thepresence of fixed concentration of GLP-1 (9-36).

GLP-1R CRE-bla CHO-K1 cells cultured in growth medium (DMEM-Highglucose, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM Hepes, 100 U/mLpenicillin/100 μg/mL streptomycin, 5 μg/mL Blasticidin, 600 μg/mLHygromycin) were trypsinized and plated in suspension into 384 wellwhite flat bottom plates at 5000 cells/well in 12 μL assay buffer (HanksBalanced Salt solution, 10 mM hepes, 0.1% BSA, pH 7.4). A 5× compounddose response curve (12-point) was generated in assay buffer containing1.5 mM IBMX, 4% DMSO. GLP-1(9-36) was diluted to 4.2 μM in assay buffercontaining 1.5 mM IMBX and 4% DMSO. The 5× compound dose response wasadded (3 μL), followed by 0.5 μL of GLP-1(9-36) and cells were incubatedfor 30 min at 37° C. Direct detection of cAMP was carried out usingDiscoveRx HitHunter cAMP kit according to manufacturer's instructionsand luminescence was read using a SpectraMax M5 plate reader.Luminescence was converted to total cAMP using a cAMP standard curve anddata was analyzed by non-linear regression to determine the EC₅₀ andEmax.

Peptide Sequences

GLP-1(7-36): HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(9-36):EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(7-36) was purchased fromGenScript. GLP-1(9-36) was purchased from Biopeptide Co., Inc.

Reported GLP-1 Activity

Activity data for selected GLP-1 modulators are displayed in Table 2.The EC₂₀GLP-1(9-36) PAMActivity range is denoted as follows: + denotesactivity <0.8 μM, ++ denotes activity between 0.8 and 2.5 μM, +++denotes activity between 2.5 and 5 μM, and ++++ denotes activity 5 to 10μM.

TABLE 2 COMPOUND EC₂₀ GLP-1(9-36) NUMBER PAM EC₅₀ 1 ++ 2 +++ 3 ++++ 4++++ 5 +++ 6 ++++ 7 ++++ 8 ++ 9 ++++ 10 +++ 11 ++ 13 ++ 14 +++ 15 +++ 16++++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 +++ 23 +++ 24 ++ 25 ++ 26 +++ 27++ 28 +++ 29 ++ 30 ++ 31 ++ 32 ++++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++38 ++ 39 ++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 ++ 46 ++ 47 +++ 48++++ 49 ++++ 50 +++ 51 +++ 52 ++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58+++ 59 +++ 60 +++ 61 +++ 62 +++ 63 ++ 64 ++ 65 +++ 66 +++ 67 ++ 68 +++69 ++++ 70 ++++ 71 +++ 72 ++++ 73 ++ 74 +++ 75 +++ 76 ++ 77 ++ 78 ++ 79++ 80 ++ 81 ++++ 82 ++ 83 ++ 84 ++ 85 ++ 86 ++ 87 ++ 88 ++++ 89 ++ 90+++ 91 ++ 92 ++ 93 ++++ 94 ++ 95 ++ 96 +++ 97 ++ 98 ++ 99 ++ 100 ++ 101++ 102 ++ 104 ++ 105 ++++ 106 ++ 107 ++ 108 ++ 109 ++ 110 ++ 111 ++ 112++ 113 ++ 114 ++ 115 ++ 116 ++ 117 + 118 + 119 + 120 ++ 121 ++ 122 ++123 ++ 124 ++ 125 ++ 126 ++ 127 ++ 128 ++ 129 ++ 130 + 131 ++ 132 ++ 133++ 134 ++ 135 ++ 136 ++++ 137 ++ 138 ++ 139 ++ 140 +++ 141 ++ 142 +143 + 144 ++ 145 ++ 146 +++ 147 +++ 148 ++ 149 ++ 150 ++ 151 ++ 152 ++153 ++ 154 + 155 ++ 156 ++ 157 ++ 158 + 159 ++ 160 ++ 161 ++ 162 ++ 163++ 164 ++ 165 ++ 166 ++ 167 ++ 168 ++ 169 ++++ 170 ++ 171 ++ 172 ++ 173++ 174 + 175 + 176 ++++ 177 ++ 178 ++ 179 ++++ 180 + 181 ++ 182 ++ 183++ 184 ++ 185 ++ 186 ++ 187 +++ 188 +++ 189 ++ 190 +++ 191 ++ 192 + 193++ 194 ++ 195 ++ 196 +++ 197 +++ 198 ++++ 199 ++ 200 +++ 201 +++ 202++++ 203 ++++ 204 +++ 205 ++ 206 +++ 207 +++ 208 +++ 209 ++ 210 +++ 211++++ 212 ++++ 213 +++ 214 +++ 215 +++ 216 +++ 217 ++++ 218 +++ 219 ++220 +++ 221 +++ 222 ++ 223 ++ 224 ++ 225 + 226 ++ 227 +++ 228 ++ 229 ++230 ++ 231 ++++ 232 ++ 233 +++ 234 ++++ 235 +++ 236 ++++ 237 ++ 238 ++239 ++ 240 +++ 241 ++ 242 ++ 243 ++ 244 +++ 245 ++ 246 ++ 247 ++ 248 +++249 ++++ 250 ++ 251 ++++ 252 ++++ 253 +++ 254 ++ 255 ++++ 256 ++++ 257++ 258 ++++ 259 ++ 260 + 261 +++ 262 +++ 263 ++ 264 ++ 265 ++++ 266 ++++267 ++ 268 ++ 269 ++ 270 +++ 271 ++ 272 ++ 273 ++ 274 ++ 275 ++ 276 ++277 + 278 +++ 279 ++++ 280 +++ 281 + 282 ++ 283 ++++ 284 ++ 285 ++ 286+++ 287 ++++ 288 +++ 289 +++ 291 ++ 292 ++ 293 +++ 294 ++ 295 ++ 296 ++297 + 298 + 299 + 300 + 301 ++ 302 +++ 303 ++ 304 ++ 305 ++ 306 + 307 ++308 ++ 309 + 310 + 311 ++ 312 ++ 313 ++ 314 ++ 315 ++ 316 + 317 + 318 +319 + 320 + 321 + 322 ++ 323 + 324 ++ 325 ++++ 326 + 327 + 328 + 329 ++330 ++ 331 ++ 332 ++ 333 + 334 ++ 335 ++ 336 + 337 ++ 338 ++ 339 ++ 340++ 341 + 342 ++ 343 ++ 344 + 345 + 346 ++ 347 + 348 ++ 349 + 350 + 351 +352 + 353 ++ 354 + 355 ++ 356 ++ 357 ++ 358 ++ 359 ++ 360 ++ 361 ++ 362+++ 363 ++ 364 ++ 365 +++ 366 +++ 367 ++ 368 + 369 ++ 370 ++ 371 + 372 +373 ++ 374 ++ 375 + 376 ++ 377 + 378 + 379 + 380 ++ 381 ++ 382 ++ 383+++ 384 ++++ 385 ++++ 386 ++ 387 ++++ 388 +++ 389 ++ 390 ++ 391 +++ 392+++ 393 ++ 394 +++ 395 ++ 396 + 397 +++ 398 + 399 + 400 + 401 + 402 +403 ++ 404 + 405 + 406 ++ 407 + 408 ++ 409 ++ 410 ++ 411 ++ 412 + 413++++ 414 + 415 + 416 + 417 + 418 + 419 + 420 + 421 ++ 422 + 423 ++ 424 +425 +++ 426 ++ 427 ++ 428 ++ 429 +++ 430 ++++ 431 + 432 + 433 +++ 434 ++435 ++ 436 + 437 + 438 ++++ 439 +++ 440 + 441 ++ 442 ++ 443 ++ 444 +445 + 446 ++ 447 ++ 448 + 449 ++ 450 + 451 + 452 +++ 453 ++ 454 ++ 455 +456 ++ 457 +++ 458 ++ 459 ++ 460 ++++ 461 ++ 462 ++++ 463 ++++ 464 ++++465 ++ 466 ++ 467 + 468 + 469 ++ 470 + 471 ++++ 472 ++ 473 ++++ 474 ++475 ++ 476 +++ 477 + 478 + 479 + 480 ++ 481 ++ 482 + 483 ++ 484 ++ 485++++ 486 + 487 + 488 ++ 489 ++ 490 ++ 491 + 492 ++++ 493 + 494 + 495 +496 + 497 + 498 ++ 499 + 500 ++ 501 + 502 + 503 ++ 504 +++ 505 ++ 506 ++507 ++ 508 + 509 ++ 510 +++ 511 ++ 512 + 513 + 514 + 515 + 516 + 517 +518 ++ 519 ++ 520 ++ 521 + 522 ++ 523 + 524 + 525 + 526 + 527 + 528 +529 + 530 + 531 ++ 532 + 533 + 534 ++ 535 ++++ 536 ++ 537 ++++ 538 ++++539 ++++ 540 + 541 ++ 542 + 543 + 544 + 545 + 546 ++ 547 ++ 548 + 549 +550 ++ 551 + 552 ++ 553 ++ 554 + 555 +++ 556 + 557 + 558 + 559 ++++ 560++ 561 + 562 + 563 + 564 ++ 565 ++ 566 + 567 + 568 + 569 + 570 + 571 ++572 ++ 573 ++ 574 ++ 575 +++ 576 ++ 577 +++ 578 +++ 579 + 580 + 581 ++582 ++ 583 ++++ 584 ++ 585 ++ 586 + 587 + 588 ++ 589 ++ 590 + 591 + 592++ 593 + 594 + 595 + 596 ++ 597 + 598 + 599 + 600 + 601 ++ 602 + 603 ++604 ++ 605 + 606 ++ 607 ++ 608 ++ 609 + 610 + 611 + 612 + 613 ++ 614 ++615 ++++ 616 ++ 617 + 618 ++++ 619 ++ 620 ++++ 621 +++ 622 ++ 623 ++624 + 625 + 626 + 627 + 628 ++ 629 ++ 630 + 631 ++ 632 ++ 633 ++ 634 +635 + 636 + 637 ++ 638 +++ 639 + 640 + 641 + 642 + 644 + 645 + 646 +647 + 648 ++ 649 ++ 650 + 651 + 652 + 653 + 654 + 655 ++ 656 ++ 657 ++658 + 659 + 660 ++ 661 + 662 + 663 ++ 664 +++ 665 ++ 666 ++ 667 ++ 668++ 669 ++ 670 +++ 671 +++ 672 +++ 673 ++++ 674 ++++ 675 ++++ 676 +++ 677+++ 678 ++ 679 ++ 680 ++++ 681 ++++ 682 +++ 683 ++ 684 ++++ 685 +++ 686+++ 687 +++ 688 +++ 689 +++ 690 +++ 691 +++ 692 ++++ 693 ++++ 694 +++695 +++ 696 +++ 697 +++ 698 + 699 ++++ 700 ++++ 701 +++ 702 ++ 703 + 704++ 705 ++ 706 ++ 707 ++++ 708 ++ 709 ++ 710 ++++ 711 +++ 712 ++ 713 ++714 +++ 715 +++ 716 ++ 717 ++ 718 +++ 719 ++ 720 +++ 721 ++ 722 ++ 723++ 724 ++ 725 ++ 726 ++ 727 +++ 728 ++ 729 ++ 730 +++ 731 +++ 732 ++ 733++ 734 ++ 735 ++ 736 + 737 + 738 + 739 + 740 +++ 741 +++ 742 +++ 743++++ 744 ++++ 745 ++ 746 +++ 747 +++ 748 +++ 749 ++ 750 +++ 751 +++ 752++++ 753 +++ 754 ++++ 755 +++ 756 ++++ 757 ++ 758 +++ 759 ++ 760 ++ 761+++ 762 ++++ 763 ++ 764 + 765 ++ 766 +++ 767 +++ 768 ++ 769 ++++ 770 +771 ++ 772 + 773 ++ 774 ++ 775 + 776 + 777 ++ 778 + 779 ++ 780 +++ 781+++ 782 ++ 783 ++ 784 ++++ 785 +++ 786 ++ 787 ++ 788 ++++ 789 +++ 790 ++791 ++ 792 ++ 793 ++ 794 ++ 795 + 796 + 797 ++ 798 ++ 799 ++ 800 ++++801 ++++ 802 +++ 803 ++ 804 ++ 806 ++ 807 ++++ 808 +++ 809 ++ 810 ++++811 ++ 812 ++ 813 ++ 814 ++ 815 + 816 ++ 817 ++ 818 ++ 819 +++ 820 +++821 ++ 822 +++ 823 ++ 824 + 825 + 826 +++ 827 ++ 828 + 829 ++++ 830 ++++832 +++ 833 ++++ 834 ++ 835 +++ 836 +++ 837 + 838 ++ 839 ++ 840 ++ 841++ 842 ++ 843 ++ 844 ++ 845 +++ 846 +++ 847 +++ 848 +++ 849 +++ 850 +++851 +++ 852 +++ 853 ++ 855 ++ 856 ++ 857 ++++ 858 ++ 859 +++ 860 ++ 861+++ 862 ++ 863 ++ 864 ++ 865 ++ 866 +++ 867 ++ 868 ++ 869 +++ 870 ++ 871+++ 872 ++ 873 + 874 ++ 875 ++ 876 ++ 877 ++ 878 + 879 +++ 880 + 881 ++882 ++ 883 ++++ 884 ++ 885 ++++ 886 ++ 887 + 888 ++ 889 ++ 890 ++ 891 ++892 + 893 +++ 894 ++++ 895 + 896 ++++ 897 ++++ 898 +++ 899 +++ 900 ++901 ++ 902 +++ 903 ++++ 904 +++ 905 ++++ 906 +++ 907 ++ 908 ++ 909 +++910 ++ 911 ++ 912 + 913 + 914 +++ 915 ++ 916 ++ 917 ++ 918 ++++ 919 ++++920 ++ 921 ++++ 922 ++++ 923 ++ 924 +++ 925 +++ 926 ++ 927 +++ 928 +++929 ++++ 930 ++++ 931 +++ 932 +++ 933 ++++ 934 ++++ 935 +++ 936 ++ 937++ 938 ++++ 939 +++ 940 ++ 941 +++ 942 +++ 943 ++ 944 + 945 + 946 +++947 ++ 948 +++ 949 ++ 950 ++ 951 ++ 952 +++ 953 ++ 954 ++ 955 ++++ 956+++ 957 ++ 958 ++ 959 ++ 960 ++ 961 +++ 962 ++ 963 ++++ 964 +++ 965 ++++966 ++++ 967 +++ 968 ++++ 969 +++ 970 +++ 971 +++ 972 ++++ 973 ++++ 974+++ 975 ++++ 976 +++ 977 ++++ 978 ++ 979 +++ 980 ++ 981 +++ 982 ++++ 983++++ 984 +++ 985 +++ 986 ++ 987 ++++ 988 ++++ 989 ++ 990 +++ 991 ++ 992+++ 993 +++ 994 ++ 995 ++++ 996 ++ 997 ++++ 998 +++ 999 +++ 1000 ++++1001 +++ 1002 ++ 1003 ++++ 1004 ++ 1005 ++ 1006 ++ 1007 ++ 1008 ++++1009 +++ 1010 +++ 1011 +++ 1012 +++ 1013 ++++ 1014 ++++ 1015 ++ 1016++++ 1017 +++ 1018 ++++ 1019 +++ 1020 ++++ 1021 +++ 1022 +++ 1023 +++1024 ++ 1025 ++ 1026 +++ 1027 ++++ 1028 +++ 1029 +++ 1030 ++++ 1031 +++1032 ++ 1033 ++++ 1034 +++ 1035 ++ 1036 +++ 1037 ++ 1038 +++ 1039 ++1040 ++++ 1041 ++ 1042 ++++ 1043 +++ 1044 +++ 1045 +++ 1046 ++ 1047 +++1048 +++ 1049 ++ 1050 ++ 1051 ++++ 1052 +++ 1053 +++ 1054 +++ 1055 +++

In Vivo Assays In Vivo Procedures The Oral Glucose Tolerance Test inC57Bl/6 Mice.

Fasted C57BL/6 female mice were 8-10 weeks of age. Sitagliptin,compound, or vehicle was dosed at least 1 hr prior to the oGTT. Micereceive a bolus of glucose (3 g/kg) by oral gavage (time 0). Bloodsamples are collected at frequent time intervals from the tail tip forglucose measurement (BD glucometer; Becton-Dickinson, Lincoln Park,N.J.).

The Oral Glucose Tolerance Test in Ob/Ob Mice

Fasted ob/ob female mice were 7-10 weeks of age. Sitagliptin, compound,or vehicle was dosed at least 1 hr prior to the oGTT. Mice receive abolus of glucose (0.2 g/kg) by oral gavage (time 0). Blood samples arecollected at frequent time intervals from the tail tip for glucosemeasurement (BD glucometer; Becton-Dickinson, Lincoln Park, N.J.).

The Oral Glucose Tolerance Test in Fa/Fa Rats.

The use of these compounds to lower glucose can be evaluated in ratsusing the protocol described by Pederson et. al. (Diabetes, Vol. 47,August 1998, 1253-1258). After an overnight fast, lean or obese animalsare administered oral glucose by syringe and feeding tube (1 g/kg) as a40% solution (wt/vol). Compound is dissolved and administered along withthe glucose. In control experiments, vehicle is administered along withoral glucose. Blood samples are collected from the tail veins ofconscious unrestrained rats into heparinized capillary tubes at 0 and 5,10, 20, 30, and 60 min after glucose administration. Blood samples arecentrifuged at 4° C., and plasma is stored at −20° C. until analysis forglucose and insulin measurement. Glucose levels are measured using theglucose oxidase procedure (Beckman glucose analyzer; Fullerton, Calif.).

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments. These and other changes can be made to the embodiments inlight of the above-detailed description. In general, in the followingclaims, the terms used should not be construed to limit the claims tothe specific embodiments disclosed in the specification and the claims,but should be construed to include all possible embodiments along withthe full scope of equivalents to which such claims are entitled.Accordingly, the claims are not limited by the disclosure.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20170313717A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound having the structure of Formula I-R or I-S or apharmaceutically acceptable isomer, enantiomer, racemate, salt, ester,prodrug, hydrate or solvate thereof:

wherein A is a 5-, 6- or 7-membered heterocyclyl having one, two orthree heteroatoms where each such heteroatom is independently selectedfrom O, N, and S, and where any ring atom of such heterocyclyl may beoptionally substituted with one or more of R₄; B is aryl, aralkyl,heterocyclyl, or heterocyclylalkyl; C is aryl, aralkyl, heterocyclyl orheterocyclylalkyl, and when C is aryl A and C may be taken together toform a fused bicyclic ring system between the 5-, 6- or 7-memberedheterocyclyl of A and the aryl of C; Y₁ and Y₂ are both null, or one ofY₁ or Y₂ is —NH— or —O— and the other Y₁ or Y₂ is null; Z is —C(O)— or—S(O)₂—; each R₁ is independently H or C₁₋₄ alkyl; R₂ is —OH, —O—R₈,—N(R₁)—SO₂—R₇, —NR₄₁R₄₂, —N(R₁)—(CR_(a)R_(b))_(m)—COOR₈,—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)C(O)O(R₈),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, or—N(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl, which heterocyclyl may beoptionally (singly or multiply) substituted with R₇; each R₃ and R₄ isindependently H, halo, alkyl, alkyl substituted (singly or multiply)with R₃₁, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy,aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂, —NR₁R₇, —C(O)R₇, —C(O)NR₁R₇,—NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇, —OS(O)₂R₇, —S(O)₂NR₁R₇,—NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇,—(CR_(a)R_(b))_(m)NR(CR_(a)R_(b))_(m)R₇ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈; or any two R₃ or R₄ groupson the same carbon atom taken together form oxo; each R₃₁ isindependently H, halo, hydroxyl, —NR₄₁R₄₂, or alkoxy; each R₄₀ isindependently H, R₇, alkyl which may be optionally (singly or multiply)substituted with R₇, or R₄₀ and R₁ taken together with the N atom towhich they are attached form a 3- to 7-membered heterocyclyl which maybe optionally (singly or multiply) substituted with R₇; each R₄₁ and R₄₂is independently R₄₀, —(CHR₄₀)_(n)—C(O)O—R₄₀, —(CHR₄₀)_(n)—C(O)—R₄₀,—(CH₂)_(n)—N(R₁)(R₇), aryl or heteroaryl any of which aryl or heteroarylmay be optionally (singly or multiply) substituted with R₇; or any twoR₄₁ and R₄₂ taken together with the N atom to which they are attachedform a 3- to 7-membered heterocyclyl which may be optionally (singly ormultiply) substituted with R₇; W₁ is null or-L₁-(CR_(a)R_(b))_(m)-L₁-R₆; each L₁ is independently, from the proximalto distal end of the structure of Formula I-R or I-S, null, —C(O)O—,—S(O₂)—, —S(O)—, —S—, —N(R₁)—C(O)—N(R₁)—, —(R₁)—C(O)—O—, —C(O)— or—S(O₂)—NR₁—; each R_(a) and R_(b) is independently H, halo, alkyl,alkoxy, aryl, aralkyl, heterocyclyl, heterocyclylalkyl (any of whichalkyl, alkoxy, aryl, aralkyl, heterocyclyl or heterocyclylalkyl may beoptionally (singly or multiply) substituted with R₇),—(CHR₄₀)_(m)C(O)OR₄₀, —(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀,—(CHR₄₀)_(m)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)—NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)—N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)OR₄₀, or —(CHR₄₀)_(m)—S—S—R₄₀; orany two R_(a) and R_(b) taken together with the carbon atom(s) to whichthey are attached form a cycloalkyl or heterocyclyl optionallysubstituted (singly or multiply) with R₇; or R₁ and any one of R_(a) orR_(b) taken together with the atom(s) to which they are attached formheterocyclyl optionally substituted (singly or multiply) with R₇; R₅ isR₇, —(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇, or-(-L₃-(CR_(a)R_(b))_(r)-)_(s)-L₃-R₇, wherein the carbon atoms of any twoadjacent —(CR_(a)R_(b))_(m) or —(CR_(a)R_(b))_(r) groups may be takentogether to form a double bond (—(C(R_(a))═(C(R_(a))—) or triple bond(—C≡C—); R₆ is H, alkyl, aryl, heteroaryl, heterocyclyl,heterocycloalkyl, any of which may be optionally substituted (singly ormultiply) with R₇ or —(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇; each R₇is independently R₁₀; a ring moiety selected from cycloalkyl, aryl,aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moiety isoptionally singly or multiply substituted with R₁₀; or when a carbonatom bears two R₇ groups such two R₇ groups are taken together to formoxo or thioxo, or are taken together to form a ring moiety selected fromcycloalkyl, aryl, heterocyclyl or heterocyclyl, wherein such ring moietyis optionally singly or multiply substituted with R₁₀; each R₁₀ isindependently H, halo, alkyl, haloalkyl, perhaloalkyl,—(CR_(a)R_(b))_(m)OH, —(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN,—(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈,—(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁S(O)₂R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,—(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈ or—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈; each R₈ is independently H, alkyl, aryl,—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₁ or-(-L₃-(CR_(a)R_(b))_(r)—)_(s)-L₃-R₁; L₂ is independently, from theproximal to distal end of the structure of Formula I-R or I-S, null,—O—, —OC(O)—, —NR₁—, —C(O)NR₁—, —N(R₁)—C(O)—, —S(O₂)—, —S(O)—, —S—,—C(O)— or —S(O₂)—N(R₁)—; each L₃ is independently null, —O—, or —N(R₁)—each m is independently 0, 1, 2, 3, 4, 5 or 6; each n is independently 0or 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; each r is independently2, 3, or 4; and each s is independently 1, 2, 3, or
 4. 2. The compoundof claim 1 having the following structure:


3. (canceled)
 4. The compound of claim 2 having the following structure:

5-15. (canceled)
 16. The compound of claim 4 having the followingstructure:

17-29. (canceled)
 30. The compound of claim 16 wherein m is 2, a singleR_(a) is hydrogen, each occurrence of R_(b) is hydrogen, and R₈ ishydrogen and R₁, R_(b) and R₈ are hydrogen. 31-46. (canceled)
 47. Thecompound of claim 16 wherein m is 1, R_(b) is hydrogen and R₁ and R_(a)taken together with the atoms to which they are attached form aheterocyclyl optionally substituted with R₇. 48-49. (canceled)
 50. Thecompound of claim 16 wherein m is 2, R_(b) of the second (CR_(a)R_(b))group is hydrogen and R₁ and R_(a) of the second (CR_(a)R_(b)) grouptaken together with the atoms to which they are attached form aheterocyclyl optionally substituted with R₇. 51-60. (canceled)
 61. Thecompound of claim 1 wherein R₂ is —N(R₁)—SO₂—R₈. 62-65. (canceled) 66.The compound of claim 1 wherein R₁ is hydrogen. 67-68. (canceled) 69.The compound of claim 1 wherein R₂ is —N(R₁)(R₄₂). 70-79. (canceled) 80.The compound of claim 1 wherein R₂ is—N(R₁)(CR_(a)R_(b))_(m)CON(R₁)(R₄₀). 81-82. (canceled)
 83. The compoundof claim 80 wherein m is 1, R_(b) is hydrogen and R₁ and R_(a) takentogether with the atoms to which they are attached form a heterocyclyloptionally substituted with R₇. 84-85. (canceled)
 86. The compound ofclaim 80 wherein m is 2, R_(b) of the second (CR_(a)R_(b)) group ishydrogen and R₁ and R_(a) of the second (CR_(a)R_(b)) group takentogether with the atoms to which they are attached form a heterocyclyloptionally substituted with R₇. 87-94. (canceled)
 95. The compound ofclaim 1 wherein R₂ is —N(R₁)(CR_(a)R_(b))_(m)N(R₁)C(O)OR₈. 96-97.(canceled)
 98. The compound of claim 1 wherein R₂ is—N(R₁)(CR_(a)R_(b))_(m)N(R₁)(R₇). 99-100. (canceled)
 101. The compoundof claim 1 wherein R₂ is —N(R₁)(CR_(a)R_(b))_(m)CON(R₁)heterocyclyl.102-103. (canceled)
 104. The compound of claim 1 wherein R₂ is—(CR_(a)R_(b))_(m)N(R₁)heterocyclyl. 105-106. (canceled)
 107. Thecompound of claim 1, wherein the compound has the structure of any oneof the compounds of Table 1 or a pharmaceutically acceptable isomer,enantiomer, racemate, salt, ester, prodrug, hydrate or solvate thereof.108. A pharmaceutical composition comprising a compound of claim 1together with at least one pharmaceutically acceptable carrier, diluentor excipient.
 109. A pharmaceutical combination comprising the compoundof claim 1 and a second medicament. 110-115. (canceled)
 116. A method ofactivation, potentiation, modulation or agonism of a glucagon-likepeptide 1 receptor comprising contacting the receptor with an effectiveamount of a compound of claim 1 or a pharmaceutical composition of claim108 or a pharmaceutical combination of claim
 109. 117. A method oftreatment of a malcondition in a patient for which activation,potentiation, modulation or agonism of a glucagon-like peptide 1receptor is medically indicated, comprising administering an effectiveamount of the compound of claim 1 to the patient at a frequency and fora duration of time sufficient to provide a beneficial effect to thepatient.
 118. The method of claim 117 wherein the malcondition is type Idiabetes, type II diabetes, gestational diabetes, obesity, excessiveappetite, insufficient satiety or metabolic disorder.
 119. The method ofclaim 117 wherein the malcondition is type II diabetes.